{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Immune Surveillance Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Histology, antigenicity, viral association, baseline immune status and disease stage fixed before outcome", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Immune Surveillance Hypothesis", "central_claim": "Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.", "proposed_mechanism": "Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.", "claimed_scope": "Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.", "claimed_level": [ "emergence restraint", "progression control" ], "is_conjunctive": true, "conjunctive_note": "SC1 prevention/emergence is the gate for the surveillance claim. Established-tumour immunotherapy efficacy is reported separately as SC2. Viral control, occult outgrowth and actual transformation prevention are not interchangeable." }, "rubric_routing": { "primary_rubric": "05-immunology-inflammation.md", "secondary_rubrics": [ "02-cancer-biology.md" ], "index_notes_applied": [ "SC1 prevention/emergence is the gate for the surveillance claim. Established-tumour immunotherapy efficacy is reported separately as SC2. Viral control, occult outgrowth and actual transformation prevention are not interchangeable." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Immune surveillance prevents or restrains emergence of clinical malignancy.", "subclaim_type": "necessity", "scope": "human cancers stratified by histology, viral association, immune status and stage before outcome", "claimed_scope": "human cancers stratified by histology, viral association, immune status and stage before outcome", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Immune-deficiency natural experiments and temporally resolved endogenous perturbations", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Timed endogenous tumour tests, antigen-specific loss/restoration, cell-resolved immune perturbations and human immune-status/adjuvant contrasts converge on restraint of clinical emergence. The human contribution varies by histology and viral status; this is a causal contribution, not universal necessity or prevention of every first mutation. Human selective nonviral nascent-cell elimination remains unmeasured, preventing a robust upstream all-system Η claim." }, { "id": "SC2", "statement": "Immune surveillance causally controls established tumours.", "subclaim_type": "necessity", "scope": "prespecified tumour types, treatment and immune contexts", "claimed_scope": "prespecified tumour types, treatment and immune contexts", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Targeted immunotherapy hard endpoints and cell-resolved dependency", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Targeted checkpoint, antigen-directed cellular therapy and vaccine interventions alter hard clinical outcomes across melanoma, lung, prostate and lymphoma, alongside independent conditional depletion/rescue systems. This establishes robust causal control capacity across interventions, with defined antigen, stage and treatment boundaries. Null vaccine and combination trials prevent predictive near-universal Θ." }, { "id": "SC3", "statement": "Immune-mediated elimination rather than equilibrium or nonimmune dormancy explains latent-cell control.", "subclaim_type": "mechanism", "scope": "occult/disseminated tumour states", "claimed_scope": "occult/disseminated tumour states", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Timed depletion, elimination readouts and dormancy contrasts", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Elimination is possible, but viable occult cells and timed dormancy breakdown directly demonstrate equilibrium; scarcity, intrinsic quiescence and niche signals also limit clearance. Thus elimination as the predominant explanation is plausible in some settings but is not established across the registered latent-cell scope." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "SC1 prevention/emergence is the gate for the surveillance claim. Established-tumour immunotherapy efficacy is reported separately as SC2. Viral control, occult outgrowth and actual transformation prevention are not interchangeable.", "primary_subclaim_id": "SC1", "aggregation_derivation": "Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Ζ", "scope_matched_would_return": "Ζ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Immune equilibrium and context-dependent editing", "core_claim": "Immune cells can suppress outgrowth while viable cells survive and escape.", "explains_what_nominal_does_not": "Immune cells can suppress outgrowth while viable cells survive and escape.", "strongest_supporting_evidence": [ "Timed dormancy, cytokine blockade and cell-transfer studies support restraint (PMID18026089, PMID33536445, PMID30598548)." ], "strongest_contradictory_evidence": [ "Some antigenic tumours are eliminated; equilibrium is not the only fate." ], "hsef_level_for_this_model": "Ζ", "rationale": "Timed dormancy, cytokine blockade and cell-transfer studies support restraint (PMID18026089, PMID33536445, PMID30598548). Some antigenic tumours are eliminated; equilibrium is not the only fate." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Immune recognition and elimination", "core_claim": "Transformed-cell recognition can remove susceptible cells and shape tumour emergence.", "explains_what_nominal_does_not": "Transformed-cell recognition can remove susceptible cells and shape tumour emergence.", "strongest_supporting_evidence": [ "Antigen-specific editing/restoration and innate receptor tests, with clinical targeted control, support causal contribution." ], "strongest_contradictory_evidence": [ "Antigen-poor tumours, incomplete clearance and null vaccine trials reject uniform sufficiency." ], "hsef_level_for_this_model": "Ζ", "rationale": "Antigen-specific editing/restoration and innate receptor tests, with clinical targeted control, support causal contribution. Antigen-poor tumours, incomplete clearance and null vaccine trials reject uniform sufficiency." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Cell-intrinsic stealth and quiescence", "core_claim": "Latent cells reduce cycling and recognition to survive.", "explains_what_nominal_does_not": "Latent cells reduce cycling and recognition to survive.", "strongest_supporting_evidence": [ "DKK1/SOX and STING/NK-related perturbations identify defined escape states (PMID27015306, PMID39106452)." ], "strongest_contradictory_evidence": [ "Timed immune depletion shows that intrinsic traits do not wholly explain control." ], "hsef_level_for_this_model": "Ε", "rationale": "DKK1/SOX and STING/NK-related perturbations identify defined escape states (PMID27015306, PMID39106452). Timed immune depletion shows that intrinsic traits do not wholly explain control." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Niche and competition-mediated dormancy", "core_claim": "Mechanical, stromal and cell-competition contexts restrain or promote residual cells.", "explains_what_nominal_does_not": "Mechanical, stromal and cell-competition contexts restrain or promote residual cells.", "strongest_supporting_evidence": [ "SPARC and stiffness perturbations change outgrowth (PMID36098678, PMID42520796)." ], "strongest_contradictory_evidence": [ "Niche mechanisms interact with immune recognition and are not generally independent of immunity." ], "hsef_level_for_this_model": "Ε", "rationale": "SPARC and stiffness perturbations change outgrowth (PMID36098678, PMID42520796). Niche mechanisms interact with immune recognition and are not generally independent of immunity." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Inflammatory or microbial promotion", "core_claim": "Some immune or microbial states accelerate tumour growth or impair therapy.", "explains_what_nominal_does_not": "Some immune or microbial states accelerate tumour growth or impair therapy.", "strongest_supporting_evidence": [ "NK VEGFA and microbial MAdCAM/regT17 manipulations show bounded promotion (PMID26873347, PMID37289890)." ], "strongest_contradictory_evidence": [ "Protective NK/T-cell contexts and targeted clinical responses preclude uniform promotion." ], "hsef_level_for_this_model": "Ε", "rationale": "NK VEGFA and microbial MAdCAM/regT17 manipulations show bounded promotion (PMID26873347, PMID37289890). Protective NK/T-cell contexts and targeted clinical responses preclude uniform promotion." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. In a defined occult lesion, serial viable-cell detection plus delayed selective resident-cell depletion distinguishes elimination from equilibrium; matched antigen-negative and intrinsic-quiescence controls distinguish immune editing from nonimmune arrest.", "study_separating_rank1_from_rank2": "In a defined occult lesion, serial viable-cell detection plus delayed selective resident-cell depletion distinguishes elimination from equilibrium; matched antigen-negative and intrinsic-quiescence controls distinguish immune editing from nonimmune arrest.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "11323675", "title": "IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.", "citation": "Shankaran V, Ikeda H, Bruce AT et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001.", "doi": "10.1038/35074122", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11323675/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11323675/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID11323675", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "what_it_does_not_show": "Constitutive immune deficiency has developmental and host-wide effects; tumour emergence does not directly observe destruction of each initial transformed clone or quantify human prevention.", "confounders_present": [ "Constitutive immune deficiency has developmental and host-wide effects; tumour emergence does not directly observe destruction of each initial transformed clone or quantify human prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "9636188", "title": "Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.", "citation": "Kaplan DH, Shankaran V, Dighe AS et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proceedings of the National Academy of Sciences of the United States of America. 1998.", "doi": "10.1073/pnas.95.13.7556", "pmcid": "PMC22681", "url": "https://pubmed.ncbi.nlm.nih.gov/9636188/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9636188/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9636188", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "what_it_does_not_show": "Global signalling and p53 sensitization affect intrinsic fitness as well as immune recognition; effects cannot all be assigned to one mature effector cell type.", "confounders_present": [ "Global signalling and p53 sensitization affect intrinsic fitness as well as immune recognition; effects cannot all be assigned to one mature effector cell type." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "10974040", "title": "Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.", "citation": "Smyth MJ, Thia KY, Street SE et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. The Journal of experimental medicine. 2000.", "doi": "10.1084/jem.192.5.755", "pmcid": "PMC2193269", "url": "https://pubmed.ncbi.nlm.nih.gov/10974040/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10974040/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID10974040", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "what_it_does_not_show": "Constitutive effector deletion has homeostatic/developmental effects; lymphoma-specific protection does not imply universal prevention or show which nascent clones were eliminated.", "confounders_present": [ "Constitutive effector deletion has homeostatic/developmental effects; lymphoma-specific protection does not imply universal prevention or show which nascent clones were eliminated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "11133760", "title": "Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.", "citation": "Street SE, Cretney E, Smyth MJ et al. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood. 2001.", "doi": "10.1182/blood.v97.1.192", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11133760/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11133760/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID11133760", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "what_it_does_not_show": "Several outcomes come from imposed tumour-cell models; constitutive genotype and strain dependence constrain broad human emergence and single-mechanism necessity.", "confounders_present": [ "Several outcomes come from imposed tumour-cell models; constitutive genotype and strain dependence constrain broad human emergence and single-mechanism necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "15007091", "title": "Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells.", "citation": "Street SE, Hayakawa Y, Zhan Y et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. The Journal of experimental medicine. 2004.", "doi": "10.1084/jem.20031981", "pmcid": "PMC2212720", "url": "https://pubmed.ncbi.nlm.nih.gov/15007091/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15007091/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15007091", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "what_it_does_not_show": "Beta2m alters several recognition pathways and cell development; transplanted-tumour rejection tests differ from native initial emergence and exact recognition pathways remained unresolved.", "confounders_present": [ "Beta2m alters several recognition pathways and cell development; transplanted-tumour rejection tests differ from native initial emergence and exact recognition pathways remained unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "18394936", "title": "NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy.", "citation": "Guerra N, Tan YX, Joncker NT et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008.", "doi": "10.1016/j.immuni.2008.02.016", "pmcid": "PMC3528789", "url": "https://pubmed.ncbi.nlm.nih.gov/18394936/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18394936/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18394936", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "what_it_does_not_show": "Constitutive receptor deletion and oncogene-transgenic backgrounds still constrain generalization; the linked correction changes an author middle initial, not the reported experiment.", "confounders_present": [ "Constitutive receptor deletion and oncogene-transgenic backgrounds still constrain generalization; the linked correction changes an author middle initial, not the reported experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "12093877", "title": "Suppression of lymphoma and epithelial malignancies effected by interferon gamma.", "citation": "Street SE, Trapani JA, MacGregor D et al. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. The Journal of experimental medicine. 2002.", "doi": "10.1084/jem.20020063", "pmcid": "PMC2194011", "url": "https://pubmed.ncbi.nlm.nih.gov/12093877/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12093877/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID12093877", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "what_it_does_not_show": "Strain-specific effects and constitutive deficiency limit specificity; shared effector genotypes and laboratory models are not fully independent causal lines.", "confounders_present": [ "Strain-specific effects and constitutive deficiency limit specificity; shared effector genotypes and laboratory models are not fully independent causal lines." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "17545627", "title": "Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma.", "citation": "Street SE, Zerafa N, Iezzi M et al. Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma. Cancer research. 2007.", "doi": "10.1158/0008-5472.CAN-06-4084", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17545627/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17545627/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17545627", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "what_it_does_not_show": "Oncogene sensitization and NK-depletion selectivity require caution; delayed clinical emergence is distinct from prevention of hyperplasia or longer survival.", "confounders_present": [ "Oncogene sensitization and NK-depletion selectivity require caution; delayed clinical emergence is distinct from prevention of hyperplasia or longer survival." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "24790144", "title": "Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice.", "citation": "Macagno M, Bandini S, Stramucci L et al. Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice. Journal of immunology (Baltimore, Md. : 1950). 2014.", "doi": "10.4049/jimmunol.1301248", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24790144/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24790144/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24790144", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice.", "what_it_does_not_show": "Increased mammary remnants reflect an embryonic developmental effect; altered tissue at risk must be separated from adult immune surveillance, while salivary growth and histology are distinct outcomes.", "confounders_present": [ "Increased mammary remnants reflect an embryonic developmental effect; altered tissue at risk must be separated from adult immune surveillance, while salivary growth and histology are distinct outcomes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "24487434", "title": "Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas.", "citation": "Afshar-Sterle S, Zotos D, Bernard NJ et al. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nature medicine. 2014.", "doi": "10.1038/nm.3442", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24487434/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24487434/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24487434", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "what_it_does_not_show": "Defined B-cell driver and murine host context establish a specific dependency, without implying every cancer or a universal immune effector module.", "confounders_present": [ "Defined B-cell driver and murine host context establish a specific dependency, without implying every cancer or a universal immune effector module." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "15951814", "title": "A critical function for type I interferons in cancer immunoediting.", "citation": "Dunn GP, Bruce AT, Sheehan KC et al. A critical function for type I interferons in cancer immunoediting. Nature immunology. 2005.", "doi": "10.1038/ni1213", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15951814/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15951814/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15951814", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "what_it_does_not_show": "Constitutive receptor changes require developmental controls; linked erratum details lack an identifier in PubMed and are not resolved here, limiting fine-detail claims.", "confounders_present": [ "Constitutive receptor changes require developmental controls; linked erratum details lack an identifier in PubMed and are not resolved here, limiting fine-detail claims." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "21930769", "title": "Type I interferon is selectively required by dendritic cells for immune rejection of tumors.", "citation": "Diamond MS, Kinder M, Matsushita H et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. The Journal of experimental medicine. 2011.", "doi": "10.1084/jem.20101158", "pmcid": "PMC3182061", "url": "https://pubmed.ncbi.nlm.nih.gov/21930769/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21930769/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21930769", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.", "what_it_does_not_show": "Highly immunogenic transplanted cells test rejection rather than initial natural transformation; Itgax targeting and chimeric compartments have defined specificity limits.", "confounders_present": [ "Highly immunogenic transplanted cells test rejection rather than initial natural transformation; Itgax targeting and chimeric compartments have defined specificity limits." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "22318521", "title": "Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.", "citation": "Matsushita H, Vesely MD, Koboldt DC et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012.", "doi": "10.1038/nature10755", "pmcid": "PMC3874809", "url": "https://pubmed.ncbi.nlm.nih.gov/22318521/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22318521/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22318521", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "what_it_does_not_show": "Carcinogen-derived and transplanted unedited clones are proxies for nascent disease; selection against antigens does not prove eradication of all early transformed cells.", "confounders_present": [ "Carcinogen-derived and transplanted unedited clones are proxies for nascent disease; selection against antigens does not prove eradication of all early transformed cells." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "22318517", "title": "Expression of tumour-specific antigens underlies cancer immunoediting.", "citation": "DuPage M, Mazumdar C, Schmidt LM et al. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012.", "doi": "10.1038/nature10803", "pmcid": "PMC3288744", "url": "https://pubmed.ncbi.nlm.nih.gov/22318517/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22318517/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22318517", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original PMC Results and Methods selected lines 103-127,130-160,163-176. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "what_it_does_not_show": "Original Results distinguish introduced LucOS antigens from native oncogenic induction: antigen tolerance gave a nonsignificant susceptibility trend, and most fresh antigenic transplants showed delay rather than rejection. Antigen re-expression restored growth restraint; the antigen-free latency contrast was not significant.", "confounders_present": [ "Original Results distinguish introduced LucOS antigens from native oncogenic induction: antigen tolerance gave a nonsignificant susceptibility trend, and most fresh antigenic transplants showed delay rather than rejection. Antigen re-expression restored growth restraint; the antigen-free latency contrast was not significant." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "LucOS/conditional-Kras-p53 platform related to lung studies 21251614 and 19010921." ] }, { "n": 15, "pmid": "21251614", "title": "Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.", "citation": "DuPage M, Cheung AF, Mazumdar C et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer cell. 2011.", "doi": "10.1016/j.ccr.2010.11.011", "pmcid": "PMC3069809", "url": "https://pubmed.ncbi.nlm.nih.gov/21251614/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21251614/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21251614", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "what_it_does_not_show": "Artificial antigenicity and different native versus transplant contexts limit generalization; untreated native tumours escaped despite continuing antigen expression.", "confounders_present": [ "Artificial antigenicity and different native versus transplant contexts limit generalization; untreated native tumours escaped despite continuing antigen expression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "19010921", "title": "Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer.", "citation": "Cheung AF, Dupage MJ, Dong HK et al. Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer. Cancer research. 2008.", "doi": "10.1158/0008-5472.CAN-08-2634", "pmcid": "PMC2597052", "url": "https://pubmed.ncbi.nlm.nih.gov/19010921/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19010921/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID19010921", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "what_it_does_not_show": "Overexpressed model antigen and tolerance engineering do not establish common human rates; demonstrates possible recognition failure rather than absence of all surveillance.", "confounders_present": [ "Overexpressed model antigen and tolerance engineering do not establish common human rates; demonstrates possible recognition failure rather than absence of all surveillance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "16136144", "title": "Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance.", "citation": "Willimsky G, Blankenstein T et al. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 2005.", "doi": "10.1038/nature03954", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16136144/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16136144/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID16136144", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "what_it_does_not_show": "Model transplantation antigens and defined driver restrict scope; direct recognition can coexist with tolerance, opposing automatic editing or elimination without excluding surveillance in other settings.", "confounders_present": [ "Model transplantation antigens and defined driver restrict scope; direct recognition can coexist with tolerance, opposing automatic editing or elimination without excluding surveillance in other settings." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "23475219", "title": "Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer.", "citation": "Rogers LM, Olivier AK, Meyerholz DK et al. Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer. Journal of immunology (Baltimore, Md. : 1950). 2013.", "doi": "10.4049/jimmunol.1203227", "pmcid": "PMC3622230", "url": "https://pubmed.ncbi.nlm.nih.gov/23475219/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23475219/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23475219", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "what_it_does_not_show": "Broad adaptive deficiency and mutagenesis architecture complicate generalization; editing without efficient clearance distinguishes restraint from universal removal.", "confounders_present": [ "Broad adaptive deficiency and mutagenesis architecture complicate generalization; editing without efficient clearance distinguishes restraint from universal removal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "26806130", "title": "Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells.", "citation": "Dadi S, Chhangawala S, Whitlock BM et al. Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells. Cell. 2016.", "doi": "10.1016/j.cell.2016.01.002", "pmcid": "PMC4733424", "url": "https://pubmed.ncbi.nlm.nih.gov/26806130/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26806130/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26806130", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "what_it_does_not_show": "IL15 has multiple developmental functions; tissue residency and growth effects require cell-resolved reconstitution before attributing every component to one mature cell population.", "confounders_present": [ "IL15 has multiple developmental functions; tissue residency and growth effects require cell-resolved reconstitution before attributing every component to one mature cell population." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "35618834", "title": "Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies.", "citation": "Kansler ER, Dadi S, Krishna C et al. Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies. Nature immunology. 2022.", "doi": "10.1038/s41590-022-01213-2", "pmcid": "PMC9202504", "url": "https://pubmed.ncbi.nlm.nih.gov/35618834/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35618834/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID35705800" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35618834", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "what_it_does_not_show": "Human survival correlations do not establish prevention; different RCC histologies and cytokine effects limit universal extrapolation, and a linked correction remains flagged. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.", "confounders_present": [ "Human survival correlations do not establish prevention; different RCC histologies and cytokine effects limit universal extrapolation, and a linked correction remains flagged. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "35444279", "title": "Programme of self-reactive innate-like T cell-mediated cancer immunity.", "citation": "Chou C, Zhang X, Krishna C et al. Programme of self-reactive innate-like T cell-mediated cancer immunity. Nature. 2022.", "doi": "10.1038/s41586-022-04632-1", "pmcid": "PMC9250102", "url": "https://pubmed.ncbi.nlm.nih.gov/35444279/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35444279/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35444279", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "what_it_does_not_show": "Transfer and engineered signalling test therapeutic capability; human cell surveys and self-antigen reactivity do not directly observe initial clone elimination in patients.", "confounders_present": [ "Transfer and engineered signalling test therapeutic capability; human cell surveys and self-antigen reactivity do not directly observe initial clone elimination in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "41043437", "title": "Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas.", "citation": "Cheung JF, Hunt BG, Wahed S et al. Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas. Cancer cell. 2025.", "doi": "10.1016/j.ccell.2025.09.005", "pmcid": "PMC12693725", "url": "https://pubmed.ncbi.nlm.nih.gov/41043437/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41043437/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41043437", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "what_it_does_not_show": "Engineered antigens and murine sarcomas narrow scope; delayed/fewer emergent tumours and antigen-negative reservoirs do not establish universal sterilizing prevention.", "confounders_present": [ "Engineered antigens and murine sarcomas narrow scope; delayed/fewer emergent tumours and antigen-negative reservoirs do not establish universal sterilizing prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "33945793", "title": "CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance.", "citation": "Wang C, Li Y, Jia L et al. CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance. Cell stem cell. 2021.", "doi": "10.1016/j.stem.2021.04.011", "pmcid": "PMC8419062", "url": "https://pubmed.ncbi.nlm.nih.gov/33945793/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33945793/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33945793", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "what_it_does_not_show": "Defined native HNSCC model and checkpoint intervention support immune control; human marker expression and sorted tumour capacity do not directly demonstrate prevention.", "confounders_present": [ "Defined native HNSCC model and checkpoint intervention support immune control; human marker expression and sorted tumour capacity do not directly demonstrate prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "40820374", "title": "Essential Role of NLRC5 in Cancer Immune Surveillance and Cancer Immunoediting.", "citation": "Shukla A, Cayarga AA, Lucier JF et al. Essential Role of NLRC5 in Cancer Immune Surveillance and Cancer Immunoediting. Scandinavian journal of immunology. 2025.", "doi": "10.1111/sji.70047", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40820374/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40820374/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40820374", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "what_it_does_not_show": "Constitutive regulator loss affects antigen presentation across compartments; chemical carcinogenesis and transplant follow-up do not establish every human histology's dependence.", "confounders_present": [ "Constitutive regulator loss affects antigen presentation across compartments; chemical carcinogenesis and transplant follow-up do not establish every human histology's dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "36706761", "title": "Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance.", "citation": "Liu X, Song J, Zhang H et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer cell. 2023.", "doi": "10.1016/j.ccell.2023.01.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36706761/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36706761/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36706761", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.", "what_it_does_not_show": "Human circulating-cell expression is observational; platelet RGS18 and HLA-E manipulations test escape from control, not ordinary human cancer emergence.", "confounders_present": [ "Human circulating-cell expression is observational; platelet RGS18 and HLA-E manipulations test escape from control, not ordinary human cancer emergence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "42520796", "title": "Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells.", "citation": "Elbanna YA, Tello-Lafoz M, Holland A et al. Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells. Immunity. 2026.", "doi": "10.1016/j.immuni.2026.06.025", "pmcid": "PMC13484358", "url": "https://pubmed.ncbi.nlm.nih.gov/42520796/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42520796/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42520796", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.", "what_it_does_not_show": "Mechanical changes also affect intrinsic metastatic fitness, and immunodeficient comparisons do not alone isolate the immune mediator; human infiltration associations remain observational.", "confounders_present": [ "Mechanical changes also affect intrinsic metastatic fitness, and immunodeficient comparisons do not alone isolate the immune mediator; human infiltration associations remain observational." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "26873347", "title": "STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion.", "citation": "Gotthardt D, Putz EM, Grundschober E et al. STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion. Cancer discovery. 2016.", "doi": "10.1158/2159-8290.CD-15-0732", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26873347/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26873347/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26873347", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.", "what_it_does_not_show": "Engineered survival rescue is not ordinary NK physiology; results oppose uniformly protective immune activation while identifying a specific pro-tumour pathway.", "confounders_present": [ "Engineered survival rescue is not ordinary NK physiology; results oppose uniformly protective immune activation while identifying a specific pro-tumour pathway." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "26384545", "title": "The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.", "citation": "Dupaul-Chicoine J, Arabzadeh A, Dagenais M et al. The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity. Immunity. 2015.", "doi": "10.1016/j.immuni.2015.08.013", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26384545/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26384545/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26384545", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.", "what_it_does_not_show": "Constitutive deficiency can affect development and other compartments; colonization and microbiome checks narrow but do not eliminate those alternatives.", "confounders_present": [ "Constitutive deficiency can affect development and other compartments; colonization and microbiome checks narrow but do not eliminate those alternatives." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "29798856", "title": "Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.", "citation": "Ma C, Han M, Heinrich B et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aan5931", "pmcid": "PMC6407885", "url": "https://pubmed.ncbi.nlm.nih.gov/29798856/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29798856/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29798856", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.", "what_it_does_not_show": "Antibiotics are pleiotropic; NKT functional dependence supports liver-specific control rather than universal benefit of microbiome depletion.", "confounders_present": [ "Antibiotics are pleiotropic; NKT functional dependence supports liver-specific control rather than universal benefit of microbiome depletion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "37289890", "title": "A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.", "citation": "Fidelle M, Rauber C, Alves Costa Silva C et al. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science (New York, N.Y.). 2023.", "doi": "10.1126/science.abo2296", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37289890/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37289890/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37289890", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.", "what_it_does_not_show": "Human serum MAdCAM prognosis does not isolate causality; results address therapy and microbial immune context rather than native transformation prevention.", "confounders_present": [ "Human serum MAdCAM prognosis does not isolate causality; results address therapy and microbial immune context rather than native transformation prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "25968569", "title": "CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome.", "citation": "Huang Y, Ma C, Zhang Q et al. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget. 2015.", "doi": "10.18632/oncotarget.3958", "pmcid": "PMC4627321", "url": "https://pubmed.ncbi.nlm.nih.gov/25968569/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25968569/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25968569", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Breast tumour models showed time-dependent CD4 subsets, while human CD8 and CD4 infiltrates associated in opposite directions with prognosis.", "what_it_does_not_show": "The abstract does not document a selective depletion contrast; subgroup timing and prognostic association cannot establish causal human protection or uniform CD4 harm.", "confounders_present": [ "The abstract does not document a selective depletion contrast; subgroup timing and prognostic association cannot establish causal human protection or uniform CD4 harm." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "38194912", "title": "Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies.", "citation": "Goddard ET, Linde MH, Srivastava S et al. Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies. Cancer cell. 2024.", "doi": "10.1016/j.ccell.2023.12.011", "pmcid": "PMC10864018", "url": "https://pubmed.ncbi.nlm.nih.gov/38194912/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38194912/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38194912", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "what_it_does_not_show": "Scarce encounters explain incomplete surveillance. Treatment-mediated elimination does not establish routine sterilizing surveillance; original body was inaccessible in this examination.", "confounders_present": [ "Scarce encounters explain incomplete surveillance. Treatment-mediated elimination does not establish routine sterilizing surveillance; original body was inaccessible in this examination." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "27015306", "title": "Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT.", "citation": "Malladi S, Macalinao DG, Jin X et al. Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell. 2016.", "doi": "10.1016/j.cell.2016.02.025", "pmcid": "PMC4808520", "url": "https://pubmed.ncbi.nlm.nih.gov/27015306/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27015306/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID27015306", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "what_it_does_not_show": "Selected human-derived cell lines and imposed dissemination establish escape capability, not frequency of native human dormancy.", "confounders_present": [ "Selected human-derived cell lines and imposed dissemination establish escape capability, not frequency of native human dormancy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "30598548", "title": "Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin.", "citation": "Park SL, Buzzai A, Rautela J et al. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature. 2019.", "doi": "10.1038/s41586-018-0812-9", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30598548/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30598548/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30742076" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30598548", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "what_it_does_not_show": "Transplantable antigenic melanoma remains a defined scope; about 40 percent macroscopic control and about 20 percent awakening after depletion show neither complete elimination nor exclusive immune dependence. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.", "confounders_present": [ "Transplantable antigenic melanoma remains a defined scope; about 40 percent macroscopic control and about 20 percent awakening after depletion show neither complete elimination nor exclusive immune dependence. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "18026089", "title": "Adaptive immunity maintains occult cancer in an equilibrium state.", "citation": "Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007.", "doi": "10.1038/nature06309", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18026089/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18026089/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18026089", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.", "what_it_does_not_show": "Abstract-level examination supports the equilibrium distinction; exact depletion timing and doses were not independently verified in original Methods.", "confounders_present": [ "Abstract-level examination supports the equilibrium distinction; exact depletion timing and doses were not independently verified in original Methods." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "33536445", "title": "CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer.", "citation": "Tallón de Lara P, Castañón H, Vermeer M et al. CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer. Nature communications. 2021.", "doi": "10.1038/s41467-021-21045-2", "pmcid": "PMC7859213", "url": "https://pubmed.ncbi.nlm.nih.gov/33536445/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33536445/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33536445", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph16, 1:Results:paragraph18, 1:Results:paragraph23, 3:Methods:paragraph5, 3:Methods:paragraph7, 3:Methods:paragraph15, 3:Methods:paragraph21. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "what_it_does_not_show": "Original Methods select 54 patients already known to relapse; the infiltrate association was not independent in multivariable Cox analysis. Native untagged priming and timed cell/cytokine perturbations support mouse dormancy, and transfer left viable noncycling cells; clinical elimination remains unproved.", "confounders_present": [ "Original Methods select 54 patients already known to relapse; the infiltrate association was not independent in multivariable Cox analysis. Native untagged priming and timed cell/cytokine perturbations support mouse dormancy, and transfer left viable noncycling cells; clinical elimination remains unproved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "4T1/4T07 are sister lines from one spontaneous tumour, not two independent native origins." ] }, { "n": 37, "pmid": "39106452", "title": "Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy.", "citation": "Bushnell GG, Sharma D, Wilmot HC et al. Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy. Cancer research. 2024.", "doi": "10.1158/0008-5472.CAN-24-0030", "pmcid": "PMC11474167", "url": "https://pubmed.ncbi.nlm.nih.gov/39106452/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39106452/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37873211" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39106452", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "what_it_does_not_show": "Transplanted cell lines and model-specific dependencies narrow generalization; human estrogen-positive lifetime recurrence is background rather than direct prospective mediator evidence.", "confounders_present": [ "Transplanted cell lines and model-specific dependencies narrow generalization; human estrogen-positive lifetime recurrence is background rather than direct prospective mediator evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "39378878", "title": "Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis.", "citation": "Dalla E, Papanicolaou M, Park MD et al. Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis. Cell. 2024.", "doi": "10.1016/j.cell.2024.09.016", "pmcid": "PMC11568918", "url": "https://pubmed.ncbi.nlm.nih.gov/39378878/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39378878/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39378878", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "what_it_does_not_show": "This restrains established disseminated cells rather than eliminating them or preventing initial transformation; tumour promotion by other macrophage states remains compatible.", "confounders_present": [ "This restrains established disseminated cells rather than eliminating them or preventing initial transformation; tumour promotion by other macrophage states remains compatible." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "40044852", "title": "Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.", "citation": "Yang J, Yamashita-Kanemaru Y, Morris BI et al. Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity. Nature. 2025.", "doi": "10.1038/s41586-025-08626-7", "pmcid": "PMC12018268", "url": "https://pubmed.ncbi.nlm.nih.gov/40044852/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40044852/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40044852", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:Aspirin releases T cells from suppression by TXA2:paragraph0, 5:Aspirin releases T cells from suppression by TXA2:paragraph1, 6:Platelet COX-1 suppresses anti-metastatic immunity:paragraph0, 6:Platelet COX-1 suppresses anti-metastatic immunity:paragraph1, 8:Methods:paragraph0, 8:Methods:paragraph1, 8:Methods:paragraph2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.", "what_it_does_not_show": "Original Methods/Results include injected B16/LL2 dissemination and native MMTV-PyMT follow-up, T-cell Arhgef1 conditional deletion, platelet COX1 loss and TXA2-analogue reversal. Effects are epistatic and model-specific; human aspirin immune mediation and initial transformation prevention are not tested.", "confounders_present": [ "Original Methods/Results include injected B16/LL2 dissemination and native MMTV-PyMT follow-up, T-cell Arhgef1 conditional deletion, platelet COX1 loss and TXA2-analogue reversal. Effects are epistatic and model-specific; human aspirin immune mediation and initial transformation prevention are not tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "36098678", "title": "Cell Competition Shapes Metastatic Latency and Relapse.", "citation": "Kim K, Huang H, Parida PK et al. Cell Competition Shapes Metastatic Latency and Relapse. Cancer discovery. 2023.", "doi": "10.1158/2159-8290.CD-22-0236", "pmcid": "PMC9839468", "url": "https://pubmed.ncbi.nlm.nih.gov/36098678/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36098678/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36098678", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.", "what_it_does_not_show": "Human renal-cancer subclone associations do not prove intervention efficacy; intrinsic competition can coexist with immune restraint.", "confounders_present": [ "Human renal-cancer subclone associations do not prove intervention efficacy; intrinsic competition can coexist with immune restraint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "28606585", "title": "Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry.", "citation": "Mayor PC, Eng KH, Singel KL et al. Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. The Journal of allergy and clinical immunology. 2018.", "doi": "10.1016/j.jaci.2017.05.024", "pmcid": "PMC5723251", "url": "https://pubmed.ncbi.nlm.nih.gov/28606585/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28606585/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28606585", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies.", "what_it_does_not_show": "Registry ascertainment, genotype syndromes and infection differ from controls; absence of significant common-solid excess constrains uniform protection rather than disproving all surveillance.", "confounders_present": [ "Registry ascertainment, genotype syndromes and infection differ from controls; absence of significant common-solid excess constrains uniform protection rather than disproving all surveillance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "22045767", "title": "Spectrum of cancer risk among US solid organ transplant recipients.", "citation": "Engels EA, Pfeiffer RM, Fraumeni JF et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011.", "doi": "10.1001/jama.2011.1592", "pmcid": "PMC3310893", "url": "https://pubmed.ncbi.nlm.nih.gov/22045767/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22045767/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "US-transplant-cancer-match", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation.", "what_it_does_not_show": "Organ-specific underlying disease, surveillance and drugs are competing causes; early liver cancers can predate transplant and are not new transformation events.", "confounders_present": [ "Organ-specific underlying disease, surveillance and drugs are competing causes; early liver cancers can predate transplant and are not new transformation events." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "20150194", "title": "Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study.", "citation": "van Leeuwen MT, Webster AC, McCredie MR et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ (Clinical research ed.). 2010.", "doi": "10.1136/bmj.c570", "pmcid": "PMC2820609", "url": "https://pubmed.ncbi.nlm.nih.gov/20150194/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20150194/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "Australian-ANZDATA-transplant", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph4, 2:Results:paragraph0, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph9. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated.", "what_it_does_not_show": "Original Methods exclude the first three months of each period, leaving 7809 analysable patients from 8173 enrolled. HPV-associated site reductions were not significant in adjusted comparisons. Graft failure changes dialysis/exposures; melanoma is not a proven virus-caused cancer, and persistent risks do not exclude earlier immune effects.", "confounders_present": [ "Original Methods exclude the first three months of each period, leaving 7809 analysable patients from 8173 enrolled. HPV-associated site reductions were not significant in adjusted comparisons. Graft failure changes dialysis/exposures; melanoma is not a proven virus-caused cancer, and persistent risks do not exclude earlier immune effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "20466855", "title": "Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency?", "citation": "Vajdic CM, Mao L, van Leeuwen MT et al. Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood. 2010.", "doi": "10.1182/blood-2010-03-272351", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20466855/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20466855/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20466855", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer.", "what_it_does_not_show": "Small site-specific counts, infection and registration selection limit generalized inference; antibody and T-cell defects are not interchangeable surveillance instruments.", "confounders_present": [ "Small site-specific counts, infection and registration selection limit generalized inference; antibody and T-cell defects are not interchangeable surveillance instruments." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "11117911", "title": "Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population.", "citation": "Imai K, Matsuyama S, Miyake S et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet (London, England). 2000.", "doi": "10.1016/S0140-6736(00)03231-1", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11117911/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11117911/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "Japanese-cytotoxicity-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Baseline peripheral lymphocyte cytotoxicity predicted lower subsequent cancer incidence in a Japanese eleven-year cohort.", "what_it_does_not_show": "Sex-specific estimates were imprecise and confounding remains; peripheral isotope-release activity is not directly measured tumour-specific elimination.", "confounders_present": [ "Sex-specific estimates were imprecise and confounding remains; peripheral isotope-release activity is not directly measured tumour-specific elimination." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "16397273", "title": "Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance.", "citation": "Hayashi T, Imai K, Morishita Y et al. Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance. Cancer research. 2006.", "doi": "10.1158/0008-5472.CAN-05-2776", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16397273/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16397273/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "Japanese-cytotoxicity-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NKG2D haplotypes associated with cytotoxicity and cancer risk within the earlier Japanese cohort.", "what_it_does_not_show": "Nested sampling shares the source cohort; linkage and pleiotropy preclude treating this as a validated causal genetic instrument. An unidentified erratum remains unresolved.", "confounders_present": [ "Nested sampling shares the source cohort; linkage and pleiotropy preclude treating this as a validated causal genetic instrument. An unidentified erratum remains unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "17721103", "title": "Risk of cancers during interrupted antiretroviral therapy in the SMART study.", "citation": "Silverberg MJ, Neuhaus J, Bower M et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS (London, England). 2007.", "doi": "10.1097/QAD.0b013e3282ed6338", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17721103/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17721103/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17721103", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference.", "what_it_does_not_show": "The intervention jointly changes virus suppression and immune function; it supports clinical infection-linked prevention rather than uniquely isolating transformed-cell recognition.", "confounders_present": [ "The intervention jointly changes virus suppression and immune function; it supports clinical infection-linked prevention rather than uniquely isolating transformed-cell recognition." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "27870055", "title": "Cancer risks after solid organ transplantation and after long-term dialysis.", "citation": "Hortlund M, Arroyo Mühr LS, Storm H et al. Cancer risks after solid organ transplantation and after long-term dialysis. International journal of cancer. 2017.", "doi": "10.1002/ijc.30531", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27870055/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27870055/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID27870055", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers.", "what_it_does_not_show": "Dialysis-associated biology and surveillance can explain part of the overlap; independent geography does not remove the shared immune-deficiency exposure confounding.", "confounders_present": [ "Dialysis-associated biology and surveillance can explain part of the overlap; independent geography does not remove the shared immune-deficiency exposure confounding." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "35932302", "title": "Pancreatic cancer among solid organ transplant recipients in the United States.", "citation": "Tanaka T, Lynch CF, Yu KJ et al. Pancreatic cancer among solid organ transplant recipients in the United States. Journal of cancer research and clinical oncology. 2023.", "doi": "10.1007/s00432-022-04227-3", "pmcid": "PMC11797600", "url": "https://pubmed.ncbi.nlm.nih.gov/35932302/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35932302/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "US-transplant-cancer-match", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "US transplant recipients had modestly elevated pancreatic cancer incidence, especially localized head lesions and liver recipients.", "what_it_does_not_show": "Imaging detection, diabetes and organ-specific care confound attribution; this overlaps the US transplant-registry programme and is not an independent immune experiment.", "confounders_present": [ "Imaging detection, diabetes and organ-specific care confound attribution; this overlaps the US transplant-registry programme and is not an independent immune experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "26731613", "title": "Risk of Colorectal Cancer After Solid Organ Transplantation in the United States.", "citation": "Safaeian M, Robbins HA, Berndt SI et al. Risk of Colorectal Cancer After Solid Organ Transplantation in the United States. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016.", "doi": "10.1111/ajt.13549", "pmcid": "PMC5218822", "url": "https://pubmed.ncbi.nlm.nih.gov/26731613/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26731613/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "US-transplant-cancer-match", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess.", "what_it_does_not_show": "Site and regimen specificity oppose uniform risk; conditional absence of excess does not prove immune irrelevance, and source patients overlap other transplant reports.", "confounders_present": [ "Site and regimen specificity oppose uniform risk; conditional absence of excess does not prove immune irrelevance, and source patients overlap other transplant reports." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "20178100", "title": "No excess risk of follicular lymphoma in kidney transplant and HIV-related immunodeficiency.", "citation": "Vajdic CM, van Leeuwen MT, Turner JJ et al. No excess risk of follicular lymphoma in kidney transplant and HIV-related immunodeficiency. International journal of cancer. 2010.", "doi": "10.1002/ijc.25272", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20178100/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20178100/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "Australian-ANZDATA-plus-HIV", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess.", "what_it_does_not_show": "Follicular counts were small with wide intervals; subtype contrast supports restricted immunity/infection effects rather than a universal lymphoma mechanism.", "confounders_present": [ "Follicular counts were small with wide intervals; subtype contrast supports restricted immunity/infection effects rather than a universal lymphoma mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "39602110", "title": "Merkel Cell Carcinoma and Immunosuppression, UV Radiation, and Merkel Cell Polyomavirus.", "citation": "Tribble JT, Pfeiffer RM, Brownell I et al. Merkel Cell Carcinoma and Immunosuppression, UV Radiation, and Merkel Cell Polyomavirus. JAMA dermatology. 2025.", "doi": "10.1001/jamadermatol.2024.4607", "pmcid": "PMC11736500", "url": "https://pubmed.ncbi.nlm.nih.gov/39602110/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39602110/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39602110", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Registry and case-series synthesis estimated MCC burden attributable to immunosuppressing conditions, UV and polyomavirus.", "what_it_does_not_show": "Small population fractions for rare immunodeficiency do not measure immunity's general protective effect; UV and viral attributable fractions overlap and cannot be summed.", "confounders_present": [ "Small population fractions for rare immunodeficiency do not measure immunity's general protective effect; UV and viral attributable fractions overlap and cannot be summed." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "US transplant/HIV registry components can overlap earlier risk reports; UV/viral synthesis is not wholly independent." ] }, { "n": 53, "pmid": "23486550", "title": "Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study.", "citation": "Leval A, Herweijer E, Ploner A et al. Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study. Journal of the National Cancer Institute. 2013.", "doi": "10.1093/jnci/djt032", "pmcid": "PMC3614506", "url": "https://pubmed.ncbi.nlm.nih.gov/23486550/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23486550/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23486550", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Swedish HPV vaccination cohorts showed reduced genital warts, strongest when vaccination began young.", "what_it_does_not_show": "The measured endpoint is genital warts, not invasive cancer or CIN; it is an exposure/control lead and cannot carry cancer prevention on its own.", "confounders_present": [ "The measured endpoint is genital warts, not invasive cancer or CIN; it is an exposure/control lead and cannot carry cancer prevention on its own." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "34741816", "title": "The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.", "citation": "Falcaro M, Castañon A, Ndlela B et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet (London, England). 2021.", "doi": "10.1016/S0140-6736(21)02178-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34741816/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34741816/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34741816", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments.", "what_it_does_not_show": "The mediator is infection prevention, not direct recognition of transformed cells; age-period effects and screening remain natural-experiment limitations.", "confounders_present": [ "The mediator is infection prevention, not direct recognition of transformed cells; age-period effects and screening remain natural-experiment limitations." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "35149535", "title": "Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial.", "citation": "Lehtinen M, Lagheden C, Luostarinen T et al. Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial. BMJ open. 2021.", "doi": "10.1136/bmjopen-2021-050669", "pmcid": "PMC8719207", "url": "https://pubmed.ncbi.nlm.nih.gov/35149535/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35149535/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35149535", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls.", "what_it_does_not_show": "Controls combine randomized placebo and population cohorts; few events yield a very wide efficacy interval. Infection blockade is not transformed-cell surveillance alone.", "confounders_present": [ "Controls combine randomized placebo and population cohorts; few events yield a very wide efficacy interval. Infection blockade is not transformed-cell surveillance alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "20525992", "title": "Improved survival with ipilimumab in patients with metastatic melanoma.", "citation": "Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. The New England journal of medicine. 2010.", "doi": "10.1056/NEJMoa1003466", "pmcid": "PMC3549297", "url": "https://pubmed.ncbi.nlm.nih.gov/20525992/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20525992/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20525992", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.", "what_it_does_not_show": "Engineered checkpoint release demonstrates clinical control capacity, with substantial immune toxicity; it does not establish routine prevention in untreated hosts. An unidentified erratum needs qualification.", "confounders_present": [ "Engineered checkpoint release demonstrates clinical control capacity, with substantial immune toxicity; it does not establish routine prevention in untreated hosts. An unidentified erratum needs qualification." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "20818862", "title": "Sipuleucel-T immunotherapy for castration-resistant prostate cancer.", "citation": "Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England journal of medicine. 2010.", "doi": "10.1056/NEJMoa1001294", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20818862/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20818862/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20818862", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.", "what_it_does_not_show": "Immune response and survival are not interchangeable with progression or mediation; the treatment is engineered and not ordinary surveillance.", "confounders_present": [ "Immune response and survival are not interchangeable with progression or mediation; the treatment is engineered and not ordinary surveillance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "26028407", "title": "Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.", "citation": "Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. The New England journal of medicine. 2015.", "doi": "10.1056/NEJMoa1504627", "pmcid": "PMC4681400", "url": "https://pubmed.ncbi.nlm.nih.gov/26028407/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26028407/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26028407", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.", "what_it_does_not_show": "Open-label treatment and previously treated disease narrow scope; receptor blockade provides targeted causal capacity without proving natural emergence prevention.", "confounders_present": [ "Open-label treatment and previously treated disease narrow scope; receptor blockade provides targeted causal capacity without proving natural emergence prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "26412456", "title": "Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.", "citation": "Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. The New England journal of medicine. 2015.", "doi": "10.1056/NEJMoa1507643", "pmcid": "PMC5705936", "url": "https://pubmed.ncbi.nlm.nih.gov/26412456/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26412456/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26412456", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.", "what_it_does_not_show": "Long-term tail and medians differ; established treated tumours are not nascent transformed-cell emergence, and clinical benefit does not alone prove every mediator step.", "confounders_present": [ "Long-term tail and medians differ; established treated tumours are not nascent transformed-cell emergence, and clinical benefit does not alone prove every mediator step." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "39282897", "title": "Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma.", "citation": "Wolchok JD, Chiarion-Sileni V, Rutkowski P et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2025.", "doi": "10.1056/NEJMoa2407417", "pmcid": "PMC12080919", "url": "https://pubmed.ncbi.nlm.nih.gov/39282897/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39282897/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39282897", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 2:Results:paragraph0, 2:Results:paragraph18. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.", "what_it_does_not_show": "Original Methods identify 945 randomized patients and powered nivolumab-containing versus ipilimumab comparisons; combination versus nivolumab and melanoma-specific survival were descriptive/post hoc. Three-year landmark survivors are selected after treatment, and survival is not verified sterilizing clearance.", "confounders_present": [ "Original Methods identify 945 randomized patients and powered nivolumab-containing versus ipilimumab comparisons; combination versus nivolumab and melanoma-specific survival were descriptive/post hoc. Three-year landmark survivors are selected after treatment, and survival is not verified sterilizing clearance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Ten-year follow-up of CheckMate067; not a new randomized cohort." ] }, { "n": 61, "pmid": "38452313", "title": "Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study.", "citation": "Luke JJ, Ascierto PA, Khattak MA et al. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024.", "doi": "10.1200/JCO.23.02355", "pmcid": "PMC11095869", "url": "https://pubmed.ncbi.nlm.nih.gov/38452313/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38452313/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38452313", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.", "what_it_does_not_show": "This causally restrains residual-disease outgrowth, not the first transformed cell; survival benefit and elimination of every dormant cell are not established by these endpoints.", "confounders_present": [ "This causally restrains residual-disease outgrowth, not the first transformed cell; survival benefit and elimination of every dormant cell are not established by these endpoints." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Final endpoint update of KEYNOTE716; not a new trial." ] }, { "n": 62, "pmid": "40623279", "title": "Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study.", "citation": "Kamdar M, Solomon SR, Arnason J et al. Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2025.", "doi": "10.1200/JCO-25-00399", "pmcid": "PMC12352567", "url": "https://pubmed.ncbi.nlm.nih.gov/40623279/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40623279/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40623279", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.", "what_it_does_not_show": "Unadjusted overall-survival confidence intervals included no effect, with extensive crossover; adjusted estimates are model-dependent. Engineered antigen recognition supports control capacity.", "confounders_present": [ "Unadjusted overall-survival confidence intervals included no effect, with extensive crossover; adjusted estimates are model-dependent. Engineered antigen recognition supports control capacity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Three-year TRANSFORM update; not a new trial." ] }, { "n": 63, "pmid": "28844499", "title": "Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial.", "citation": "Weller M, Butowski N, Tran DD et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. The Lancet. Oncology. 2017.", "doi": "10.1016/S1470-2045(17)30517-X", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28844499/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28844499/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28844499", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.", "what_it_does_not_show": "A failed antigen/vaccine regimen constrains general treatment sufficiency, not the existence of immune tumour control in other contexts.", "confounders_present": [ "A failed antigen/vaccine regimen constrains general treatment sufficiency, not the existence of immune tumour control in other contexts." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "35998300", "title": "Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma.", "citation": "Chesney JA, Ribas A, Long GV et al. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023.", "doi": "10.1200/JCO.22.00343", "pmcid": "PMC9870217", "url": "https://pubmed.ncbi.nlm.nih.gov/35998300/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35998300/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35998300", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.", "what_it_does_not_show": "Incremental combination failure is not failure of the active checkpoint backbone or proof against immune surveillance.", "confounders_present": [ "Incremental combination failure is not failure of the active checkpoint backbone or proof against immune surveillance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "24019551", "title": "Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor > 1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial.", "citation": "Eggermont AM, Suciu S, Rutkowski P et al. Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor > 1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013.", "doi": "10.1200/JCO.2012.47.9303", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24019551/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24019551/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24019551", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping.", "what_it_does_not_show": "Later overall-survival intervals included no effect. Antibody induction is not proof of beneficial transformed-cell killing or a sufficient clinical endpoint.", "confounders_present": [ "Later overall-survival intervals included no effect. Antibody induction is not proof of beneficial transformed-cell killing or a sufficient clinical endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 69, "verified": 69, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Rubric05 admits targeted clinical therapy, inborn-immunity natural experiments and incidence/depletion endpoints. Broad suppression alone does not cross Δ; timed native immune tests and antigen loss/restoration do. Human adjuvant recurrence prevention directly tests emergence from residual cells, while HPV vaccination tests infection prevention and is not substituted for transformed-cell sensing. These classes fail differently and are scored as a convergent set; neither an unethical prevention-RCT requirement nor a weakest-member cap is imposed. SC3 is an unmet positive elimination-dominance burden, not a literal Gamma hard rule.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID11323675, PMID9636188, PMID10974040, PMID11133760, PMID15007091, PMID18394936, PMID12093877, PMID17545627, PMID24790144, PMID24487434, PMID15951814, PMID22318521, PMID22318517, PMID21251614, PMID19010921, PMID16136144, PMID23475219, PMID26806130, PMID35618834, PMID35444279, PMID41043437, PMID33945793, PMID40820374, PMID18026089, PMID28606585, PMID22045767, PMID20150194, PMID20466855, PMID17721103, PMID27870055, PMID26731613, PMID20178100, PMID34741816, PMID35149535, PMID38452313", "gamma_hard_rules_triggered": [ "Broad-deficiency legs are qualified; timed and antigen-specific native tests cover their weaknesses." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Timed endogenous tumour tests, antigen-specific loss/restoration, cell-resolved immune perturbations and human immune-status/adjuvant contrasts converge on restraint of clinical emergence. The human contribution varies by histology and viral status; this is a causal contribution, not universal necessity or prevention of every first mutation. Human selective nonviral nascent-cell elimination remains unmeasured, preventing a robust upstream all-system Η claim.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID11323675, PMID9636188, PMID10974040, PMID11133760, PMID15007091, PMID18394936, PMID12093877, PMID17545627, PMID24487434, PMID15951814, PMID21930769, PMID22318521, PMID22318517, PMID21251614, PMID19010921, PMID16136144, PMID23475219, PMID26806130, PMID35618834, PMID35444279, PMID41043437, PMID33945793, PMID40820374, PMID36706761, PMID42520796, PMID26873347, PMID26384545, PMID29798856, PMID37289890, PMID38194912, PMID27015306, PMID30598548, PMID33536445, PMID39106452, PMID39378878, PMID40044852, PMID36098678, PMID20525992, PMID20818862, PMID26028407, PMID26412456, PMID39282897, PMID38452313, PMID40623279, PMID28844499, PMID35998300, PMID24019551", "gamma_hard_rules_triggered": [ "Targeted clinical endpoints and orthogonal receptor/cell manipulations exceed biomarker association." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Targeted checkpoint, antigen-directed cellular therapy and vaccine interventions alter hard clinical outcomes across melanoma, lung, prostate and lymphoma, alongside independent conditional depletion/rescue systems. This establishes robust causal control capacity across interventions, with defined antigen, stage and treatment boundaries. Null vaccine and combination trials prevent predictive near-universal Θ.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID38194912, PMID27015306, PMID30598548, PMID18026089, PMID33536445, PMID39106452, PMID39378878, PMID36098678", "gamma_hard_rules_triggered": [ "Clearance predominance lacks direct human demonstration; equilibrium is positively demonstrated." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Elimination is possible, but viable occult cells and timed dormancy breakdown directly demonstrate equilibrium; scarcity, intrinsic quiescence and niche signals also limit clearance. Thus elimination as the predominant explanation is plausible in some settings but is not established across the registered latent-cell scope.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[9] Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[35] Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.", "[41] USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies.", "[42] Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation.", "[43] Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated.", "[44] Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer.", "[47] Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference.", "[48] Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers.", "[50] US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess.", "[51] Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess.", "[54] English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments.", "[55] Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[9] Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[35] Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.", "[41] USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies.", "[42] Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation.", "[43] Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated.", "[44] Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer.", "[47] Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference.", "[48] Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers.", "[50] US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess.", "[51] Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess.", "[54] English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments.", "[55] Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[9] Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[35] Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.", "[41] USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies.", "[42] Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation.", "[43] Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated.", "[44] Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer.", "[47] Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference.", "[48] Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers.", "[50] US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess.", "[51] Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess.", "[54] English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments.", "[55] Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires robust upstream causal evidence across systems and interventions.", "satisfied": "no", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[9] Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[35] Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.", "[41] USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies.", "[42] Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation.", "[43] Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated.", "[44] Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer.", "[47] Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference.", "[48] Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers.", "[50] US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess.", "[51] Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess.", "[54] English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments.", "[55] Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection." ], "what_would_cross_it": "Independent prospective human antigen/immune mediator tracing before clinical emergence, with a selective perturbation or rigorous natural instrument, shows early nonviral-cell restraint beyond infection prevention and across prespecified tissue settings." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[12] DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[25] HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.", "[26] Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.", "[27] NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.", "[28] Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.", "[29] Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.", "[30] Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.", "[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "[39] T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.", "[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.", "[56] Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.", "[57] Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.", "[58] Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.", "[59] Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.", "[60] CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.", "[62] Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.", "[63] ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.", "[64] Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.", "[65] GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[12] DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[25] HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.", "[26] Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.", "[27] NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.", "[28] Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.", "[29] Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.", "[30] Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.", "[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "[39] T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.", "[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.", "[56] Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.", "[57] Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.", "[58] Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.", "[59] Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.", "[60] CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.", "[62] Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.", "[63] ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.", "[64] Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.", "[65] GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[12] DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[25] HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.", "[26] Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.", "[27] NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.", "[28] Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.", "[29] Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.", "[30] Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.", "[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "[39] T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.", "[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.", "[56] Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.", "[57] Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.", "[58] Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.", "[59] Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.", "[60] CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.", "[62] Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.", "[63] ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.", "[64] Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.", "[65] GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires robust upstream causal evidence across systems and interventions.", "satisfied": "yes", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[12] DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[25] HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.", "[26] Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.", "[27] NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.", "[28] Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.", "[29] Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.", "[30] Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.", "[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "[39] T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.", "[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.", "[56] Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.", "[57] Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.", "[58] Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.", "[59] Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.", "[60] CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.", "[62] Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.", "[63] ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.", "[64] Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.", "[65] GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Θ", "requirement_quoted": "Requires predictive consistency and minimal contradiction in the claimed disease scope.", "satisfied": "no", "supporting_evidence": [ "[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.", "[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.", "[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.", "[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.", "[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.", "[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.", "[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.", "[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.", "[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.", "[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.", "[12] DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.", "[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.", "[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.", "[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.", "[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.", "[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.", "[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.", "[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.", "[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.", "[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.", "[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.", "[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.", "[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.", "[25] HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.", "[26] Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.", "[27] NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.", "[28] Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.", "[29] Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.", "[30] Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.", "[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "[39] T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.", "[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.", "[56] Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.", "[57] Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.", "[58] Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.", "[59] Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.", "[60] CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.", "[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.", "[62] Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.", "[63] ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.", "[64] Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.", "[65] GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping." ], "what_would_cross_it": "Prespecified antigen/context models predict response and nonresponse across independently held-out tumour settings with few unexplained failures; complete necessity and sufficiency require dedicated elimination/rescue tests." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [ "[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.", "[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.", "[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.", "[35] Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.", "[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.", "[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.", "[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.", "[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse." ], "what_would_cross_it": "Serial viable-cell quantification distinguishes actual elimination from arrest, then timed selective depletion tests for residual outgrowth with nonimmune dormancy controls." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Antigen-negative and specific-tolerance comparisons; restored tumour-antigen expression.", "Timed depletion after initiation, plus viability/outgrowth rather than macroscopic absence.", "Matched immune-competent/deficient hosts and cell-specific cytokine/effector manipulations.", "Infection-associated versus unrelated cancer types and nonreversing post-failure risks.", "Randomized active/placebo clinical comparators and failed vaccine/combination regimens." ], "note": "Native and transplanted mouse models, human immune-status exposures and randomized therapies cover distinct contexts. Antigenicity, stage, virus status, histology and cell state explain much heterogeneity; these are baseline scopes, not selected responder definitions. No count of prevented human transformation events or universal elimination frequency is inferred." }, "falsification_patterns_met": [ { "pattern": "Antigen-poor native tumours develop despite intact immunity", "evidence": "PMID16136144 and PMID23475219 limit automatic surveillance and uniform recognition.", "downgrade_applied": false, "note": "Already included in context and higher-threshold assessment." }, { "pattern": "Dormant viable cells survive under protective immunity", "evidence": "PMID18026089, PMID30598548 and PMID33536445 reject elimination-exclusive control.", "downgrade_applied": false, "note": "SC3 limits stated without duplicate nominal penalty." }, { "pattern": "Immune manipulation can fail or promote cancer", "evidence": "PMID26873347, PMID28844499, PMID35998300 and PMID24019551 constrain uniform therapeutic benefit.", "downgrade_applied": false, "note": "Included in Theta audit and scope, without repeated downgrade." } ], "pitfalls_flagged": [ { "pitfall": "Macroscopic tumour-free status treated as elimination", "where": "Equilibrium and residual dissemination models." }, { "pitfall": "Virus prevention equated with transformed-cell sensing", "where": "HPV vaccine, HIV and transplant incidence evidence." }, { "pitfall": "Established immunotherapy benefit treated as natural prevention frequency", "where": "Checkpoint and CAR-T trials." }, { "pitfall": "Immune activation always called protective", "where": "NK VEGFA and regulatory trafficking." }, { "pitfall": "Provider or publication counts treated as independent evidence", "where": "Consensus screen counts, shared cohorts and repeated endpoints." } ], "causal_tally_audit": { "tally_claimed_by_document": 59, "tally_after_audit": 59, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "GW vaccination is an infection-control lead, not a cancer endpoint.", "A native induced tumour can still carry introduced antigen.", "Specific antigen tolerance and adjusted HPV comparisons include nonsignificant results; neither is overstated." ] }, "steelman": { "case_one_rung_higher": "Η for SC1 is defensible if the combination of native selective recognition tests, clinical residual-disease prevention and natural human exposure reversibility is judged to resolve upstream emergence across systems. It remains blocked here by missing direct early nonviral human recognition attribution; progression capacity cannot simply supply that step.", "case_one_rung_lower": "Ε would restrict the claim to one context despite independently targeted native, innate/adaptive and human hard-endpoint perturbations that exclude a downstream-marker-only account. The registered statement is causal suppression, not universal elimination.", "which_rejected": "Ζ balances convergent causal restraint with incomplete direct human emergence mediation. SC2 earns Η; SC3 Γ is explicitly separate and does not redefine suppresses as sterilizes.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Prospectively trace antigen-defined premalignant clones in a prespecified high-risk human tissue and pair serial viable-cell/immune-contact measures with a narrowly targeted, ethically acceptable interception or rigorous natural immune-pathway contrast." }, "final_score": { "hsef_level": "Ζ", "hsef_descriptor": "Multiple independent causal lines converge", "confidence": "Moderate", "confidence_rationale": "65 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Immune recognition is an extrinsic protective causal restraint: it can prevent outgrowth, maintain equilibrium or eliminate susceptible cells, while failed recognition and promotional immune states permit progression. It is not a universal initiator of cancer; the role vocabulary describes stabilization of the nonmalignant/dormant state.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named programmes in this corpus — conditional platelet COX1/TXA2-ARHGEF1 epistasis, microbial MAdCAM and regT17 trafficking manipulation, and SPARC/stiffness dormancy perturbation — test mechanistic and functional boundaries. No presently recruiting study addressing the SC1 Eta boundary check, prospective human tracing or interception of nonviral nascent clones before clinical emergence, is identified.", "justification": "The named programmes in this corpus — conditional platelet COX1/TXA2-ARHGEF1 epistasis, microbial MAdCAM and regT17 trafficking manipulation, and SPARC/stiffness dormancy perturbation — test mechanistic and functional boundaries. No presently recruiting study addressing the SC1 Eta boundary check, prospective human tracing or interception of nonviral nascent clones before clinical emergence, is identified." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Ζ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Ζ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Prospectively trace antigen-defined premalignant clones in a prespecified high-risk human tissue and pair serial viable-cell/immune-contact measures with a narrowly targeted, ethically acceptable interception or rigorous natural immune-pathway contrast.", "readout": "Clone survival, malignant conversion, immune engagement and subsequent clinical emergence", "critical_control": "Baseline antigen-negative clones, virus status, intrinsic growth traits and surveillance intensity; distinguish viable dormancy from absent detection", "supporting_result": "Selective recognition engagement reduces conversion/outgrowth with a mediator-consistent contrast and independent replication", "falsifying_result": "Engagement changes immune markers without clone fate or clinical emergence, or nonimmune traits fully explain the contrast" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Direct measurement of human nonviral nascent-cell recognition before diagnosis.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Validated viable-cell markers separating elimination from equilibrium.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Predictive receptor/antigen rules for protective versus promotional immune states.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Independent human immune instruments separated from infection, drug carcinogenicity and detection.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Low-toxicity interception trials with hard emergence endpoints and predefined safety/net benefit.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Mechanism-specific recurrence outcomes that distinguish persistent dormancy from cure.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-05", "reviewer": "Codex", "evidence_base_note": "65 primary reports; literature cutoff 2026-10-05; source examination UTC date 2026-10-06; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Europe PMC; signed-in Consensus browser discovery and attempted indexed full-text extraction. Successful passages and failures are reconciled with original sections where available; see case reconciliation. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": false, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Inborn-immunity contrasts, immune-status reversibility, ART randomization, adjuvant PD1 control and targeted checkpoint/CAR-T trials make upper levels reachable. SC1 crosses Ζ as causal restraint, but direct selective early human nonviral recognition remains unresolved for Η; SC2 crosses Η, while reproducible failures and incomplete antigen predictability stop Θ. No universal necessity/sufficiency claim crosses Ω." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Inborn-immunity contrasts, immune-status reversibility, ART randomization, adjuvant PD1 control and targeted checkpoint/CAR-T trials make upper levels reachable. SC1 crosses Ζ as causal restraint, but direct selective early human nonviral recognition remains unresolved for Η; SC2 crosses Η, while reproducible failures and incomplete antigen predictability stop Θ. No universal necessity/sufficiency claim crosses Ω." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Inborn-immunity contrasts, immune-status reversibility, ART randomization, adjuvant PD1 control and targeted checkpoint/CAR-T trials make upper levels reachable. SC1 crosses Ζ as causal restraint, but direct selective early human nonviral recognition remains unresolved for Η; SC2 crosses Η, while reproducible failures and incomplete antigen predictability stop Θ. No universal necessity/sufficiency claim crosses Ω." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Inborn-immunity contrasts, immune-status reversibility, ART randomization, adjuvant PD1 control and targeted checkpoint/CAR-T trials make upper levels reachable. SC1 crosses Ζ as causal restraint, but direct selective early human nonviral recognition remains unresolved for Η; SC2 crosses Η, while reproducible failures and incomplete antigen predictability stop Θ. No universal necessity/sufficiency claim crosses Ω." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Inborn-immunity contrasts, immune-status reversibility, ART randomization, adjuvant PD1 control and targeted checkpoint/CAR-T trials make upper levels reachable. SC1 crosses Ζ as causal restraint, but direct selective early human nonviral recognition remains unresolved for Η; SC2 crosses Η, while reproducible failures and incomplete antigen predictability stop Θ. No universal necessity/sufficiency claim crosses Ω." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 65, "claims_total": 69, "claims_verified": 69, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 65, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity. Constitutive immune deficiency has developmental and host-wide effects; tumour emergence does not directly observe destruction of each initial transformed clone or quantify human prevention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C2", "text": "IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity. Global signalling and p53 sensitization affect intrinsic fitness as well as immune recognition; effects cannot all be assigned to one mature effector cell type.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C3", "text": "Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged. Constitutive effector deletion has homeostatic/developmental effects; lymphoma-specific protection does not imply universal prevention or show which nascent clones were eliminated.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C4", "text": "Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models. Several outcomes come from imposed tumour-cell models; constitutive genotype and strain dependence constrain broad human emergence and single-mechanism necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C5", "text": "Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection. Beta2m alters several recognition pathways and cell development; transplanted-tumour rejection tests differ from native initial emergence and exact recognition pathways remained unresolved.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C6", "text": "NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures. Constitutive receptor deletion and oncogene-transgenic backgrounds still constrain generalization; the linked correction changes an author middle initial, not the reported experiment.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C7", "text": "Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice. Strain-specific effects and constitutive deficiency limit specificity; shared effector genotypes and laboratory models are not fully independent causal lines.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C8", "text": "Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin. Oncogene sensitization and NK-depletion selectivity require caution; delayed clinical emergence is distinct from prevention of hyperplasia or longer survival.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C9", "text": "Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice. Increased mammary remnants reflect an embryonic developmental effect; altered tissue at risk must be separated from adult immune surveillance, while salivary growth and histology are distinct outcomes.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C10", "text": "T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand. Defined B-cell driver and murine host context establish a specific dependency, without implying every cancer or a universal immune effector module.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C11", "text": "Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer. Constitutive receptor changes require developmental controls; linked erratum details lack an identifier in PubMed and are not resolved here, limiting fine-detail claims.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C12", "text": "DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement. Highly immunogenic transplanted cells test rejection rather than initial natural transformation; Itgax targeting and chimeric compartments have defined specificity limits.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C13", "text": "Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2. Carcinogen-derived and transplanted unedited clones are proxies for nascent disease; selection against antigens does not prove eradication of all early transformed cells.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C14", "text": "Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss. Original Results distinguish introduced LucOS antigens from native oncogenic induction: antigen tolerance gave a nonsignificant susceptibility trend, and most fresh antigenic transplants showed delay rather than rejection. Antigen re-expression restored growth restraint; the antigen-free latency contrast was not significant.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original PMC Results and Methods selected lines 103-127,130-160,163-176. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C15", "text": "Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss. Artificial antigenicity and different native versus transplant contexts limit generalization; untreated native tumours escaped despite continuing antigen expression.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C16", "text": "A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells. Overexpressed model antigen and tolerance engineering do not establish common human rates; demonstrates possible recognition failure rather than absence of all surveillance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C17", "text": "Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them. Model transplantation antigens and defined driver restrict scope; direct recognition can coexist with tolerance, opposing automatic editing or elimination without excluding surveillance in other settings.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C18", "text": "Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles. Broad adaptive deficiency and mutagenesis architecture complicate generalization; editing without efficient clearance distinguishes restraint from universal removal.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C19", "text": "Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence. IL15 has multiple developmental functions; tissue residency and growth effects require cell-resolved reconstitution before attributing every component to one mature cell population.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C20", "text": "Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations. Human survival correlations do not establish prevention; different RCC histologies and cytokine effects limit universal extrapolation, and a linked correction remains flagged. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C21", "text": "Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth. Transfer and engineered signalling test therapeutic capability; human cell surveys and self-antigen reactivity do not directly observe initial clone elimination in patients.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C22", "text": "Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas. Engineered antigens and murine sarcomas narrow scope; delayed/fewer emergent tumours and antigen-negative reservoirs do not establish universal sterilizing prevention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C23", "text": "CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells. Defined native HNSCC model and checkpoint intervention support immune control; human marker expression and sorted tumour capacity do not directly demonstrate prevention.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C24", "text": "Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing. Constitutive regulator loss affects antigen presentation across compartments; chemical carcinogenesis and transplant follow-up do not establish every human histology's dependence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C25", "text": "HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems. Human circulating-cell expression is observational; platelet RGS18 and HLA-E manipulations test escape from control, not ordinary human cancer emergence.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C26", "text": "Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity. Mechanical changes also affect intrinsic metastatic fitness, and immunodeficient comparisons do not alone isolate the immune mediator; human infiltration associations remain observational.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C27", "text": "NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2. Engineered survival rescue is not ordinary NK physiology; results oppose uniformly protective immune activation while identifying a specific pro-tumour pathway.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C28", "text": "Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function. Constitutive deficiency can affect development and other compartments; colonization and microbiome checks narrow but do not eliminate those alternatives.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C29", "text": "Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control. Antibiotics are pleiotropic; NKT functional dependence supports liver-specific control rather than universal benefit of microbiome depletion.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C30", "text": "Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy. Human serum MAdCAM prognosis does not isolate causality; results address therapy and microbial immune context rather than native transformation prevention.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C31", "text": "Breast tumour models showed time-dependent CD4 subsets, while human CD8 and CD4 infiltrates associated in opposite directions with prognosis. The abstract does not document a selective depletion contrast; subgroup timing and prognostic association cannot establish causal human protection or uniform CD4 harm.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C32", "text": "Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems. Scarce encounters explain incomplete surveillance. Treatment-mediated elimination does not establish routine sterilizing surveillance; original body was inaccessible in this examination.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C33", "text": "SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance. Selected human-derived cell lines and imposed dissemination establish escape capability, not frequency of native human dormancy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C34", "text": "Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells. Transplantable antigenic melanoma remains a defined scope; about 40 percent macroscopic control and about 20 percent awakening after depletion show neither complete elimination nor exclusive immune dependence. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C35", "text": "Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape. Abstract-level examination supports the equilibrium distinction; exact depletion timing and doses were not independently verified in original Methods.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C36", "text": "TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth. Original Methods select 54 patients already known to relapse; the infiltrate association was not independent in multivariable Cox analysis. Native untagged priming and timed cell/cytokine perturbations support mouse dormancy, and transfer left viable noncycling cells; clinical elimination remains unproved.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph16, 1:Results:paragraph18, 1:Results:paragraph23, 3:Methods:paragraph5, 3:Methods:paragraph7, 3:Methods:paragraph15, 3:Methods:paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C37", "text": "Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells. Transplanted cell lines and model-specific dependencies narrow generalization; human estrogen-positive lifetime recurrence is background rather than direct prospective mediator evidence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C38", "text": "Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening. This restrains established disseminated cells rather than eliminating them or preventing initial transformation; tumour promotion by other macrophage states remains compatible.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C39", "text": "T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects. Original Methods/Results include injected B16/LL2 dissemination and native MMTV-PyMT follow-up, T-cell Arhgef1 conditional deletion, platelet COX1 loss and TXA2-analogue reversal. Effects are epistatic and model-specific; human aspirin immune mediation and initial transformation prevention are not tested.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:Aspirin releases T cells from suppression by TXA2:paragraph0, 5:Aspirin releases T cells from suppression by TXA2:paragraph1, 6:Platelet COX-1 suppresses anti-metastatic immunity:paragraph0, 6:Platelet COX-1 suppresses anti-metastatic immunity:paragraph1, 8:Methods:paragraph0, 8:Methods:paragraph1, 8:Methods:paragraph2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C40", "text": "SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse. Human renal-cancer subclone associations do not prove intervention efficacy; intrinsic competition can coexist with immune restraint.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C41", "text": "USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies. Registry ascertainment, genotype syndromes and infection differ from controls; absence of significant common-solid excess constrains uniform protection rather than disproving all surveillance.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C42", "text": "Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation. Organ-specific underlying disease, surveillance and drugs are competing causes; early liver cancers can predate transplant and are not new transformation events.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C43", "text": "Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated. Original Methods exclude the first three months of each period, leaving 7809 analysable patients from 8173 enrolled. HPV-associated site reductions were not significant in adjusted comparisons. Graft failure changes dialysis/exposures; melanoma is not a proven virus-caused cancer, and persistent risks do not exclude earlier immune effects.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph4, 2:Results:paragraph0, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph9. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C44", "text": "Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer. Small site-specific counts, infection and registration selection limit generalized inference; antibody and T-cell defects are not interchangeable surveillance instruments.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C45", "text": "Baseline peripheral lymphocyte cytotoxicity predicted lower subsequent cancer incidence in a Japanese eleven-year cohort. Sex-specific estimates were imprecise and confounding remains; peripheral isotope-release activity is not directly measured tumour-specific elimination.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C46", "text": "NKG2D haplotypes associated with cytotoxicity and cancer risk within the earlier Japanese cohort. Nested sampling shares the source cohort; linkage and pleiotropy preclude treating this as a validated causal genetic instrument. An unidentified erratum remains unresolved.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C47", "text": "Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference. The intervention jointly changes virus suppression and immune function; it supports clinical infection-linked prevention rather than uniquely isolating transformed-cell recognition.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C48", "text": "Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers. Dialysis-associated biology and surveillance can explain part of the overlap; independent geography does not remove the shared immune-deficiency exposure confounding.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C49", "text": "US transplant recipients had modestly elevated pancreatic cancer incidence, especially localized head lesions and liver recipients. Imaging detection, diabetes and organ-specific care confound attribution; this overlaps the US transplant-registry programme and is not an independent immune experiment.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C50", "text": "US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess. Site and regimen specificity oppose uniform risk; conditional absence of excess does not prove immune irrelevance, and source patients overlap other transplant reports.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C51", "text": "Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess. Follicular counts were small with wide intervals; subtype contrast supports restricted immunity/infection effects rather than a universal lymphoma mechanism.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C52", "text": "Registry and case-series synthesis estimated MCC burden attributable to immunosuppressing conditions, UV and polyomavirus. Small population fractions for rare immunodeficiency do not measure immunity's general protective effect; UV and viral attributable fractions overlap and cannot be summed.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C53", "text": "Swedish HPV vaccination cohorts showed reduced genital warts, strongest when vaccination began young. The measured endpoint is genital warts, not invasive cancer or CIN; it is an exposure/control lead and cannot carry cancer prevention on its own.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C54", "text": "English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments. The mediator is infection prevention, not direct recognition of transformed cells; age-period effects and screening remain natural-experiment limitations.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C55", "text": "Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls. Controls combine randomized placebo and population cohorts; few events yield a very wide efficacy interval. Infection blockade is not transformed-cell surveillance alone.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C56", "text": "Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine. Engineered checkpoint release demonstrates clinical control capacity, with substantial immune toxicity; it does not establish routine prevention in untreated hosts. An unidentified erratum needs qualification.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C57", "text": "Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time. Immune response and survival are not interchangeable with progression or mediation; the treatment is engineered and not ordinary surveillance.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C58", "text": "Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC. Open-label treatment and previously treated disease narrow scope; receptor blockade provides targeted causal capacity without proving natural emergence prevention.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C59", "text": "Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival. Long-term tail and medians differ; established treated tumours are not nascent transformed-cell emergence, and clinical benefit does not alone prove every mediator step.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C60", "text": "CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab. Original Methods identify 945 randomized patients and powered nivolumab-containing versus ipilimumab comparisons; combination versus nivolumab and melanoma-specific survival were descriptive/post hoc. Three-year landmark survivors are selected after treatment, and survival is not verified sterilizing clearance.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 2:Results:paragraph0, 2:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C61", "text": "Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection. This causally restrains residual-disease outgrowth, not the first transformed cell; survival benefit and elimination of every dormant cell are not established by these endpoints.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C62", "text": "Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL. Unadjusted overall-survival confidence intervals included no effect, with extensive crossover; adjusted estimates are model-dependent. Engineered antigen recognition supports control capacity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C63", "text": "ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population. A failed antigen/vaccine regimen constrains general treatment sufficiency, not the existence of immune tumour control in other contexts.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C64", "text": "Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases. Incremental combination failure is not failure of the active checkpoint backbone or proof against immune surveillance.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C65", "text": "GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping. Later overall-survival intervals included no effect. Antibody induction is not proof of beneficial transformed-cell killing or a sufficient clinical endpoint.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC1", "text": "Timed endogenous tumour tests, antigen-specific loss/restoration, cell-resolved immune perturbations and human immune-status/adjuvant contrasts converge on restraint of clinical emergence. The human contribution varies by histology and viral status; this is a causal contribution, not universal necessity or prevention of every first mutation. Human selective nonviral nascent-cell elimination remains unmeasured, preventing a robust upstream all-system Η claim.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 35, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC2", "text": "Targeted checkpoint, antigen-directed cellular therapy and vaccine interventions alter hard clinical outcomes across melanoma, lung, prostate and lymphoma, alongside independent conditional depletion/rescue systems. This establishes robust causal control capacity across interventions, with defined antigen, stage and treatment boundaries. Null vaccine and combination trials prevent predictive near-universal Θ.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC3", "text": "Elimination is possible, but viable occult cells and timed dormancy breakdown directly demonstrate equilibrium; scarcity, intrinsic quiescence and niche signals also limit clearance. Thus elimination as the predominant explanation is plausible in some settings but is not established across the registered latent-cell scope.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 32, 33, 34, 35, 36, 37, 38, 40 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CH", "text": "Immune recognition causally restrains cancer emergence and progression in defined contexts; elimination, equilibrium and escape are distinct outcomes.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 13, 14, 43, 61, 60, 36 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-06", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Shankaran V, Ikeda H, Bruce AT et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001.", "tier": "A", "kind": "primary", "pmid": "11323675", "doi": "10.1038/35074122", "url": "https://pubmed.ncbi.nlm.nih.gov/11323675/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID11323675", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2" ] }, { "n": 2, "citation": "Kaplan DH, Shankaran V, Dighe AS et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proceedings of the National Academy of Sciences of the United States of America. 1998.", "tier": "A", "kind": "primary", "pmid": "9636188", "doi": "10.1073/pnas.95.13.7556", "url": "https://pubmed.ncbi.nlm.nih.gov/9636188/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9636188", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC2" ] }, { "n": 3, "citation": "Smyth MJ, Thia KY, Street SE et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. The Journal of experimental medicine. 2000.", "tier": "A", "kind": "primary", "pmid": "10974040", "doi": "10.1084/jem.192.5.755", "url": "https://pubmed.ncbi.nlm.nih.gov/10974040/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID10974040", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC2" ] }, { "n": 4, "citation": "Street SE, Cretney E, Smyth MJ et al. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood. 2001.", "tier": "A", "kind": "primary", "pmid": "11133760", "doi": "10.1182/blood.v97.1.192", "url": "https://pubmed.ncbi.nlm.nih.gov/11133760/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID11133760", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC2" ] }, { "n": 5, "citation": "Street SE, Hayakawa Y, Zhan Y et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. The Journal of experimental medicine. 2004.", "tier": "A", "kind": "primary", "pmid": "15007091", "doi": "10.1084/jem.20031981", "url": "https://pubmed.ncbi.nlm.nih.gov/15007091/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15007091", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC2" ] }, { "n": 6, "citation": "Guerra N, Tan YX, Joncker NT et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008.", "tier": "A", "kind": "primary", "pmid": "18394936", "doi": "10.1016/j.immuni.2008.02.016", "url": "https://pubmed.ncbi.nlm.nih.gov/18394936/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18394936", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC2" ] }, { "n": 7, "citation": "Street SE, Trapani JA, MacGregor D et al. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. 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No complete-paper or supplement audit claimed.", "carries_claims": [ "C65", "CSC2" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Native antigen and timing", "sources": [ 14, 13, 35 ], "excludes_error": "Separates recognition/editing/equilibrium from transplantation capacity, though induced mouse antigens remain scope-limited." }, { "label": "Innate receptor and cell pathways", "sources": [ 6, 19, 39 ], "excludes_error": "Tests mechanisms with failure modes distinct from adaptive antigen assays." }, { "label": "Human immune-status reversibility", "sources": [ 43, 41, 47 ], "excludes_error": "Tests clinical emergence across exposure classes; infection and underlying disease remain confounders." }, { "label": "Targeted human residual and established control", "sources": [ 61, 60, 58, 62 ], "excludes_error": "Randomization and distinct clinical receptor/antigen targets exclude a purely observational or downstream-marker explanation." } ], "shared_failure_mode_checked": true, "note": "65 reports do not mean 65 independent causal lines. Registry overlap, one Japanese cohort, shared murine lineage/antigen platforms and repeated trial follow-up are identified. Orthogonal timing, antigen restoration, innate pathways and human clinical perturbations support convergence without pooling them as an incidence fraction." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Ζ", "hsef_descriptor": "Multiple independent causal lines converge", "confidence": "Moderate", "confidence_rationale": "65 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument." }, "score_after": { "hsef_level": "Ζ", "hsef_descriptor": "Multiple independent causal lines converge", "confidence": "Moderate", "confidence_rationale": "65 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\immune-surveillance-cancer\\consensus\\browser-proof.png", "sha256": "ef1eec362ac5cc9a554d10d897e4ce66ca846b3bd6e7206cb5f007799fda72c5" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\immune-surveillance-cancer\\consensus\\browser-provenance.json", "sha256": "c76aa66610ca059eb60accc91f26a1a84e7ec7515d3e48f1110ae4d9999c5b92" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\immune-surveillance-cancer\\consensus\\deep-dom.txt", "sha256": "60bb12c17ba2dca1d3ebdcbb92e8d829040ace3efadb13318a9bf16cc02deb3e" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\immune-surveillance-cancer\\consensus\\deep-response.txt", "sha256": "0d5bd021ece8937d251f414a3cd71ada834532d26cbce9433cefa7ca35587650" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\immune-surveillance-cancer\\consensus\\pro-dom.txt", "sha256": "a20bb51252787a481894b2ad96dff4d755fb921842eb4f2261d0f04a8778db2b" } ], "limitations": "This verifies documented historical use and links the record to the final edition. 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