{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Immunoediting (elim–equil–escape)", "entry_form": "phenomenon", "gradeable_restatement": "The immune system actively sculpts tumors, driving all developing tumors through an obligate sequence of elimination, equilibrium and escape while selecting immune-resistant variants.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Tumor etiology, host immune genotype, baseline antigen repertoire, stage and untreated versus therapy-selected setting", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Immunoediting (elim–equil–escape)", "central_claim": "The immune system actively sculpts tumors, driving all developing tumors through an obligate sequence of elimination, equilibrium and escape while selecting immune-resistant variants.", "proposed_mechanism": "The immune system actively sculpts tumors, driving all developing tumors through an obligate sequence of elimination, equilibrium and escape while selecting immune-resistant variants.", "claimed_scope": "Every developing human tumor, with etiology and stage fixed before outcomes; scoped immune selection is a separate burden.", "claimed_level": [ "initiation", "progression", "mechanism" ], "is_conjunctive": true, "conjunctive_note": "Use the index universal-sequence form; SC6 gates that scope. Elimination, equilibrium and different escape substrates are scored separately, including immunogenic versus low-burden etiologies. HLA loss is not evidence of point-mutational neoantigen depletion." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "05-immunology-inflammation.md" ], "index_notes_applied": [ "Use the index universal-sequence form; SC6 gates that scope. Elimination, equilibrium and different escape substrates are scored separately, including immunogenic versus low-burden etiologies. HLA loss is not evidence of point-mutational neoantigen depletion." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Adaptive immunity eliminates nascent transformed cells in vivo.", "subclaim_type": "necessity", "scope": "defined host immune genotype and cancer etiology", "claimed_scope": "defined host immune genotype and cancer etiology", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Endogenous immune loss/restoration with tumor phenotype", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Lymphocyte/IFNgamma loss, DC-specific IFNAR1 deletion, antigen tolerance and effector transfer change tumor emergence/rejection (PMID11323675,21930769,22318517,12093876). Orthogonal contrasts support Ζ in specified etiologies. Perforin-insensitive Myc lymphoma and KPC outgrowth prevent universal Η." }, { "id": "SC2", "statement": "Adaptive immunity maintains occult transformed cells in equilibrium.", "subclaim_type": "necessity", "scope": "defined occult-tumor model and follow-up", "claimed_scope": "defined occult-tumor model and follow-up", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Delayed immune interruption and lineage-confirmed outgrowth", "hsef_level": "Δ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Koebel reports transformed occult cells under prolonged immune restraint and later edited spontaneous escape in chemical carcinogenesis (PMID18026089), supporting Δ within that model. Only its complete primary abstract was accessible; exact body/supplement intervention frequencies remain unverified. Therapeutic CTL-induced arrest (PMID25127875) is not independent spontaneous equilibrium." }, { "id": "SC3", "statement": "Untreated tumor escape occurs through point-mutational neoantigen depletion under selection.", "subclaim_type": "mechanism", "scope": "untreated tumors and baseline antigen repertoire", "claimed_scope": "untreated tumors and baseline antigen repertoire", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Clone/antigen-resolved selection contrasts", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Matsushita tracks selection of pre-existing mutant-spectrin-negative clones and restores antigen-dependent rejection (PMID22318521). Treatment-naive 2026 cSCC adds clonal restriction with purity/growth and HLA controls (PMID42276071). Context-matched nulls undermine uncorrected pan-cancer depletion (PMID31768072). This supports Ε in mapped antigen/clonal contexts, not all untreated tumors." }, { "id": "SC4", "statement": "Immune selection causes loss of antigen-presentation capacity including HLA LOH.", "subclaim_type": "mechanism", "scope": "immune genotype, tumor etiology and genomic state", "claimed_scope": "immune genotype, tumor etiology and genomic state", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Presentation restoration and immune-dependent clonal selection", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Autochthonous model-antigen/MHC contrasts, serial human autologous recognition/B2M loss, clonal organoid–TIL assays and allele-specific HLA evolution converge (PMID22318517,25294904,40614739,29107330). Defined presentation escape reaches Ζ. Not every HLA event is functionally restored or isolated from passenger CIN." }, { "id": "SC5", "statement": "Reversible epigenetic neoantigen silencing mediates immune escape.", "subclaim_type": "mechanism", "scope": "locus, clone and methylation state", "claimed_scope": "locus, clone and methylation state", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Antigen-expression restoration and recognition rescue", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Aza restores DuPage reporter antigen expression; Rosenthal methylation associates with non-expression (PMID22318517,30894752). A naturally silenced mutant human locus with presentation/recognition rescue is not established by the examined passages. SETDB1 TE-antigen/MHC/CD8 epistasis under therapy is a distinct broader mechanism (PMID33953401). Exact SC5 stays Γ." }, { "id": "SC6", "statement": "Every developing human tumor follows the obligate three-phase sequence.", "subclaim_type": "generalization", "scope": "human cancer etiologies/stages determined before outcomes", "claimed_scope": "human cancer etiologies/stages determined before outcomes", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Prospective untreated inception cohorts plus causal phase transitions", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "No all-etiology human inception study identifies the obligatory sequence. Sustained validated juvenile T-cell depletion leaves KPC onset/survival intact, with OVA positive control (PMID27642636); early CRC escape and innate editing delimit phase generalization (PMID41193656,22927549). Human universal sequence inference remains Β." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use the index universal-sequence form; SC6 gates that scope. Elimination, equilibrium and different escape substrates are scored separately, including immunogenic versus low-burden etiologies. HLA loss is not evidence of point-mutational neoantigen depletion.", "primary_subclaim_id": "SC6", "aggregation_derivation": "SC6 gates the registered universal scope and remains Β. Human phase histories are chiefly inferred from sampled lesions/genomes without an all-etiology causal inception dataset. This does not cap scoped immune elimination or presentation escape, which reach Ζ through matching genetic and functional contrasts. Low-antigen KPC, innate-only editing and early evasion delimit the universal inference.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Β", "scope_matched_would_return": "Β", "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": "Etiology-stratified immune editing", "core_claim": "Baseline antigenicity, lineage and immunity determine editing routes.", "explains_what_nominal_does_not": "Baseline antigenicity, lineage and immunity determine editing routes.", "strongest_supporting_evidence": [ "MCA/antigen causal contrasts, KPC and human cSCC/NSCLC (PMID22318521,27642636,42276071)." ], "strongest_contradictory_evidence": [ "Earliest human transition frequencies remain unresolved; scope cannot be chosen after outcomes." ], "hsef_level_for_this_model": "Ζ", "rationale": "MCA/antigen causal contrasts, KPC and human cSCC/NSCLC (PMID22318521,27642636,42276071). Earliest human transition frequencies remain unresolved; scope cannot be chosen after outcomes." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Antigen-presentation attrition", "core_claim": "Mutations can persist while HLA/B2M presentation or recognition fails.", "explains_what_nominal_does_not": "Mutations can persist while HLA/B2M presentation or recognition fails.", "strongest_supporting_evidence": [ "Autologous recognition, model MHC selection and organoid assays (PMID22318517,25294904,40614739)." ], "strongest_contradictory_evidence": [ "Different defects/shared cohorts do not verify every HLA event." ], "hsef_level_for_this_model": "Ζ", "rationale": "Autologous recognition, model MHC selection and organoid assays (PMID22318517,25294904,40614739). Different defects/shared cohorts do not verify every HLA event." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Immunological ignorance", "core_claim": "Expressed antigens need not recruit effective specific recognition.", "explains_what_nominal_does_not": "Expressed antigens need not recruit effective specific recognition.", "strongest_supporting_evidence": [ "Retained melanoma epitopes without reactive clones, vaccine-broadened responses and KPC positive control (PMID31685621,27642636)." ], "strongest_contradictory_evidence": [ "Sampling may miss reactive clones; no detected response is not no historical pressure." ], "hsef_level_for_this_model": "Ε", "rationale": "Retained melanoma epitopes without reactive clones, vaccine-broadened responses and KPC positive control (PMID31685621,27642636). Sampling may miss reactive clones; no detected response is not no historical pressure." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Innate/myeloid pre-emption", "core_claim": "Lineage and early suppressive niches permit outgrowth before effective adaptive engagement.", "explains_what_nominal_does_not": "Lineage and early suppressive niches permit outgrowth before effective adaptive engagement.", "strongest_supporting_evidence": [ "Innate-only editing and IL1/SOX2 precancer intervention (PMID22927549,42446924)." ], "strongest_contradictory_evidence": [ "No prior brief equilibrium is not traced across all systems." ], "hsef_level_for_this_model": "Ε", "rationale": "Innate-only editing and IL1/SOX2 precancer intervention (PMID22927549,42446924). No prior brief equilibrium is not traced across all systems." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Universal obligatory three phases", "core_claim": "All developing human tumors require sequential adaptive elimination, equilibrium and escape.", "explains_what_nominal_does_not": "All developing human tumors require sequential adaptive elimination, equilibrium and escape.", "strongest_supporting_evidence": [ "Classical mouse phases are a serious steelman (PMID11323675,18026089,22318517)." ], "strongest_contradictory_evidence": [ "No causal human all-phase dataset; low-antigen and early-escape contrasts constrain extrapolation." ], "hsef_level_for_this_model": "Β", "rationale": "Classical mouse phases are a serious steelman (PMID11323675,18026089,22318517). No causal human all-phase dataset; low-antigen and early-escape contrasts constrain extrapolation." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. KPC sustained prediagnostic T-cell depletion with repeated verification and an engineered OVA positive control separates universal necessity from baseline-antigen-dependent editing (PMID27642636).", "study_separating_rank1_from_rank2": "KPC sustained prediagnostic T-cell depletion with repeated verification and an engineered OVA positive control separates universal necessity from baseline-antigen-dependent editing (PMID27642636).", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "40645187", "title": "TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak.", "citation": "Rozalén C, Sangrador I, Avalle S et al. TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak. Cancer cell. 2025.", "doi": "10.1016/j.ccell.2025.06.015", "pmcid": "PMC12416865", "url": "https://pubmed.ncbi.nlm.nih.gov/40645187/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40645187/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40645187", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Breast micrometastasis mouse models plus human comparison", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Tumor TIM3 perturbation links stemness, suppressive gamma-delta cells and metastatic seeding", "what_it_does_not_show": "Metastatic context and multifunctional signaling; no obligatory inception sequence", "confounders_present": [ "Metastatic context and multifunctional signaling; no obligatory inception sequence" ], "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": "31645760", "title": "MHC-II neoantigens shape tumour immunity and response to immunotherapy.", "citation": "Alspach E, Lussier DM, Miceli AP et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature. 2019.", "doi": "10.1038/s41586-019-1671-8", "pmcid": "PMC6858572", "url": "https://pubmed.ncbi.nlm.nih.gov/31645760/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31645760/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31645760", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Mouse spontaneous and therapy-induced rejection", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Both antigen-specific CD4 and CD8 responses contribute to rejection with local class-II antigen requirements", "what_it_does_not_show": "Scoped antigens and models; not all human tumors", "confounders_present": [ "Scoped antigens and models; not all human tumors" ], "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": "35589842", "title": "Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.", "citation": "Łuksza M, Sethna ZM, Rojas LA et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature. 2022.", "doi": "10.1038/s41586-022-04735-9", "pmcid": "PMC9177421", "url": "https://pubmed.ncbi.nlm.nih.gov/35589842/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35589842/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35589842", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "70 pancreatic cancers with recurrent disease over ten years", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "High-quality neoantigen loss and clonal fitness model support selection in long survivors", "what_it_does_not_show": "Survivor selection and recurrence; inference rather than experimental untreated initiation", "confounders_present": [ "Survivor selection and recurrence; inference rather than experimental untreated initiation" ], "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": "27183590", "title": "NKG2D-NKG2D Ligand Interaction Inhibits the Outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo.", "citation": "Raju S, Kretzmer LZ, Koues OI et al. NKG2D-NKG2D Ligand Interaction Inhibits the Outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo. Journal of immunology (Baltimore, Md. : 1950). 2016.", "doi": "10.4049/jimmunol.1501982", "pmcid": "PMC4875802", "url": "https://pubmed.ncbi.nlm.nih.gov/27183590/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27183590/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27183590", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "NKG2D-deficient aging mice and human lymphoma comparison", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NKG2D ligand recognition restrains naturally arising B-cell tumors", "what_it_does_not_show": "Innate pathway; grade-dependent human association not universal adaptive sequence", "confounders_present": [ "Innate pathway; grade-dependent human association not universal adaptive sequence" ], "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": "31141692", "title": "The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer.", "citation": "De Mattos-Arruda L, Sammut SJ, Ross EM et al. The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. Cell reports. 2019.", "doi": "10.1016/j.celrep.2019.04.098", "pmcid": "PMC6546974", "url": "https://pubmed.ncbi.nlm.nih.gov/31141692/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31141692/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31141692", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "Ten therapy-resistant breast cancer autopsies", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Multiregional HLA loss and TCR patterns accompany lethal metastatic evolution", "what_it_does_not_show": "Heavily treated endpoint sampling; no untreated inception or phase causality", "confounders_present": [ "Heavily treated endpoint sampling; no untreated inception or phase causality" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Carcinogen sarcomas and spontaneous epithelial tumors in immune-deficient mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Lymphocytes and IFNgamma suppress tumors and select less immunogenic variants", "what_it_does_not_show": "Broad immune deficiency and specific etiologies; every tumor sequence not established", "confounders_present": [ "Broad immune deficiency and specific etiologies; every tumor sequence not established" ], "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": "25127875", "title": "Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFNγ-dependent cell-cycle arrest.", "citation": "Matsushita H, Hosoi A, Ueha S et al. Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFNγ-dependent cell-cycle arrest. Cancer immunology research. 2015.", "doi": "10.1158/2326-6066.CIR-14-0098", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25127875/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25127875/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25127875", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Transferred TCR-transgenic CTLs and B16-fucci tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "IFNgamma neutralization reverses growth arrest; arrest can dominate lysis", "what_it_does_not_show": "Adoptive therapy and differing IFNgamma sensitivity; not spontaneous occult equilibrium", "confounders_present": [ "Adoptive therapy and differing IFNgamma sensitivity; not spontaneous occult equilibrium" ], "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": "26321679", "title": "Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.", "citation": "Chang CH, Qiu J, O'Sullivan D et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015.", "doi": "10.1016/j.cell.2015.08.016", "pmcid": "PMC4864363", "url": "https://pubmed.ncbi.nlm.nih.gov/26321679/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26321679/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26321679", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Antigenic mouse sarcoma glycolysis perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Tumor glucose competition can override T-cell protection and impair effector function", "what_it_does_not_show": "Metabolic suppression permits antigen-retaining escape; engineered pathway sufficiency", "confounders_present": [ "Metabolic suppression permits antigen-retaining escape; engineered pathway sufficiency" ], "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": "25428507", "title": "Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.", "citation": "Gubin MM, Zhang X, Schuster H et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014.", "doi": "10.1038/nature13988", "pmcid": "PMC4279952", "url": "https://pubmed.ncbi.nlm.nih.gov/25428507/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25428507/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25428507", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Mouse sarcoma checkpoint blockade and peptide vaccines", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Mutant-antigen-specific T cells reactivate and vaccination rejects tumors", "what_it_does_not_show": "Therapeutically augmented rejection; not untreated universal selection", "confounders_present": [ "Therapeutically augmented rejection; not untreated universal selection" ], "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": "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 in the PubMed record" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "Type-I interferon deficient mouse tumor experiments", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Host hematopoietic IFN responses protect against primary and transplanted tumors", "what_it_does_not_show": "Broad pathway; linked erratum notice lacks resolved PMID/details", "confounders_present": [ "Broad pathway; linked erratum notice lacks resolved PMID/details" ], "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": "28445461", "title": "Tumour ischaemia by interferon-γ resembles physiological blood vessel regression.", "citation": "Kammertoens T, Friese C, Arina A et al. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature. 2017.", "doi": "10.1038/nature22311", "pmcid": "PMC5567674", "url": "https://pubmed.ncbi.nlm.nih.gov/28445461/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28445461/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28445461", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Defined-cell IFNgamma receptor mice with established vascular tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Endothelial responsiveness is necessary and sufficient for induced ischemic regression", "what_it_does_not_show": "Induced IFNgamma in established tumors; not nascent elimination or equilibrium", "confounders_present": [ "Induced IFNgamma in established tumors; not nascent elimination or equilibrium" ], "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": "30894752", "title": "Neoantigen-directed immune escape in lung cancer evolution.", "citation": "Rosenthal R, Cadieux EL, Salgado R et al. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019.", "doi": "10.1038/s41586-019-1032-7", "pmcid": "PMC6954100", "url": "https://pubmed.ncbi.nlm.nih.gov/30894752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30894752/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30894752", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph13, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4", "SC5", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "258 regions from 88 untreated early NSCLC tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Immune context associates with copy-number antigen loss, HLA dysfunction and neoantigen promoter methylation", "what_it_does_not_show": "Shared TRACERx; methylation association does not demonstrate demethylation/recognition rescue", "confounders_present": [ "Shared TRACERx; methylation association does not demonstrate demethylation/recognition rescue" ], "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": [ "Shared TRACERx cohort/platform; distinct assay or analysis is not independent population replication." ] }, { "n": 13, "pmid": "29855388", "title": "Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome.", "citation": "Zapata L, Pich O, Serrano L et al. Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome. Genome biology. 2018.", "doi": "10.1186/s13059-018-1434-0", "pmcid": "PMC5984361", "url": "https://pubmed.ncbi.nlm.nih.gov/29855388/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29855388/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29855388", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "7546 TCGA exomes across 26 types", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Empirical sequence analyses suggest negative selection in immune-exposed regions", "what_it_does_not_show": "Null mutation context, expression and prediction biases matter; no immune intervention", "confounders_present": [ "Null mutation context, expression and prediction biases matter; no immune intervention" ], "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": "32162254", "title": "Characterizing MHC-I Genotype Predictive Power for Oncogenic Mutation Probability in Cancer Patients.", "citation": "Beauchemin L, Slifker M, Rossell D et al. Characterizing MHC-I Genotype Predictive Power for Oncogenic Mutation Probability in Cancer Patients. Methods in molecular biology (Clifton, N.J.). 2020.", "doi": "10.1007/978-1-0716-0389-5_8", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32162254/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32162254/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32162254", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "9176 TCGA tumors and 1018 recurrent mutations", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MHC genotype presentation scores predict mutation probabilities", "what_it_does_not_show": "Computational association; genotype and mutation processes may confound selection", "confounders_present": [ "Computational association; genotype and mutation processes may confound selection" ], "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": 15, "pmid": "29107330", "title": "Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.", "citation": "McGranahan N, Rosenthal R, Hiley CT et al. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell. 2017.", "doi": "10.1016/j.cell.2017.10.001", "pmcid": "PMC5720478", "url": "https://pubmed.ncbi.nlm.nih.gov/29107330/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29107330/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29107330", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph29, 1:Results:paragraph30, 1:Results:paragraph65. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Multiregional untreated NSCLC TRACERx plus TCGA", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Allele-specific HLA loss is focal, often subclonal, and linked to lost-allele-binding neoantigens", "what_it_does_not_show": "Loss of presenter does not delete antigen mutation; cohort overlap and CIN passenger alternatives", "confounders_present": [ "Loss of presenter does not delete antigen mutation; cohort overlap and CIN passenger 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": [ "Shared TRACERx cohort/platform; distinct assay or analysis is not independent population replication." ] }, { "n": 16, "pmid": "39358601", "title": "MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.", "citation": "Puttick C, Jones TP, Leung MM et al. MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution. Nature genetics. 2024.", "doi": "10.1038/s41588-024-01883-8", "pmcid": "PMC11525181", "url": "https://pubmed.ncbi.nlm.nih.gov/39358601/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39358601/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39358601", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Lung TRACERx and lung/breast TCGA transcriptomics", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "HLA repression/splicing and LOH refine effective neoantigen burden and metastasis associations", "what_it_does_not_show": "Shared cohorts and transcriptomic disruption; not universal sequence or functional restoration", "confounders_present": [ "Shared cohorts and transcriptomic disruption; not universal sequence or functional restoration" ], "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": [ "Shared TRACERx cohort/platform; distinct assay or analysis is not independent population replication." ] }, { "n": 17, "pmid": "40614739", "title": "Subclonal immune evasion in non-small cell lung cancer.", "citation": "Dijkstra KK, Vendramin R, Karagianni D et al. Subclonal immune evasion in non-small cell lung cancer. Cancer cell. 2025.", "doi": "10.1016/j.ccell.2025.06.012", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40614739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40614739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID42155448" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40614739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Organoids from three TRACERx patients; 81 clonal sublines with TIL/NK assays", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Functional immune evasion differs among subclones within each tumor", "what_it_does_not_show": "Ex vivo propagation and three patients; linked 2026 correction details not audited", "confounders_present": [ "Ex vivo propagation and three patients; linked 2026 correction details not audited" ], "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": [ "Shared TRACERx cohort/platform; distinct assay or analysis is not independent population replication." ] }, { "n": 18, "pmid": "26137415", "title": "Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice.", "citation": "Pathria P, Gotthardt D, Prchal-Murphy M et al. Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice. Oncoimmunology. 2015.", "doi": "10.1080/2162402X.2014.998529", "pmcid": "PMC4485776", "url": "https://pubmed.ncbi.nlm.nih.gov/26137415/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26137415/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26137415", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Myeloid STAT3 deletion in autochthonous AOM/DSS colorectal tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Myeloid deletion reduces tumor formation with stromal T-cell activation and residual escape", "what_it_does_not_show": "Inflammatory carcinogenesis and pleiotropy; adaptive mechanism inferred partly from transplantation", "confounders_present": [ "Inflammatory carcinogenesis and pleiotropy; adaptive mechanism inferred partly from transplantation" ], "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": "39002266", "title": "Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma.", "citation": "Hong WF, Zhang F, Wang N et al. Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2024.", "doi": "10.1016/j.drup.2024.101115", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39002266/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39002266/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39002266", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "16 HR-stratified human pancreatic tissues", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Spatial macrophage SIGLEC10/CD52 axis associates with repair context", "what_it_does_not_show": "Spatial multiomics generates mechanism candidates; no obligatory sequence or definitive causal editing", "confounders_present": [ "Spatial multiomics generates mechanism candidates; no obligatory sequence or definitive causal editing" ], "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": "38815010", "title": "Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity.", "citation": "Houlahan KE, Khan A, Greenwald NF et al. Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity. Science (New York, N.Y.). 2024.", "doi": "10.1126/science.adh8697", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38815010/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38815010/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36993286" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38815010", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "5870 human breast lesions", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Germline epitope burden associates with amplified subtype incidence and cold aggressive tumors", "what_it_does_not_show": "Germline selection inference; no prospective phase transitions", "confounders_present": [ "Germline selection inference; no prospective phase transitions" ], "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": "38803565", "title": "Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma.", "citation": "Zhou Y, Mo S, Cui H et al. Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma. National science review. 2024.", "doi": "10.1093/nsr/nwae150", "pmcid": "PMC11129594", "url": "https://pubmed.ncbi.nlm.nih.gov/38803565/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38803565/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38803565", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "507 samples from 103 esophageal tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Spatial immune context and inferred subclone fitness vary along tumors", "what_it_does_not_show": "Retrospective inferred editing and expression; not phase necessity", "confounders_present": [ "Retrospective inferred editing and expression; not phase 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": 22, "pmid": "41193656", "title": "Epigenetically driven and early immune evasion in colorectal cancer evolution.", "citation": "Lakatos E, Gunasri V, Zapata L et al. Epigenetically driven and early immune evasion in colorectal cancer evolution. Nature genetics. 2025.", "doi": "10.1038/s41588-025-02349-1", "pmcid": "PMC12695633", "url": "https://pubmed.ncbi.nlm.nih.gov/41193656/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41193656/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41193656", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "495 glands from 29 colorectal tumors plus spatial microbiopsies", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Chromatin changes, antigen silencing and exclusion are inferred near transformation with little later editing", "what_it_does_not_show": "Timing inferred from sampled extant lesions; early escape contradicts assuming a long mandatory equilibrium", "confounders_present": [ "Timing inferred from sampled extant lesions; early escape contradicts assuming a long mandatory equilibrium" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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", "SC3", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Engineered fluorescent-antigen murine sarcoma", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Timed antigen removal and T-cell/IFNgamma interruption separate direct and bystander early elimination", "what_it_does_not_show": "Engineered antigens; antigen-negative cells also exist without T cells; silencing alone not sufficient", "confounders_present": [ "Engineered antigens; antigen-negative cells also exist without T cells; silencing alone not sufficient" ], "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": "40132544", "title": "Comprehensive assessment of computational methods for cancer immunoediting.", "citation": "He S, Sun S, Liu K et al. Comprehensive assessment of computational methods for cancer immunoediting. Cell reports methods. 2025.", "doi": "10.1016/j.crmeth.2025.101006", "pmcid": "PMC12049729", "url": "https://pubmed.ncbi.nlm.nih.gov/40132544/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40132544/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40132544", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "Four computational methods in colorectal TCGA and ten PDX pairs", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Editing estimates vary widely with method, neoantigen criteria and reference data", "what_it_does_not_show": "Original method comparison not causal immune editing; union of estimates is not truth validation", "confounders_present": [ "Original method comparison not causal immune editing; union of estimates is not truth validation" ], "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": "32929288", "title": "Evolutionary dynamics of neoantigens in growing tumors.", "citation": "Lakatos E, Williams MJ, Schenck RO et al. Evolutionary dynamics of neoantigens in growing tumors. Nature genetics. 2020.", "doi": "10.1038/s41588-020-0687-1", "pmcid": "PMC7610467", "url": "https://pubmed.ncbi.nlm.nih.gov/32929288/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32929288/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32929288", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "Mathematical model tested against 879 colon/stomach/endometrial datasets", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Selection/escape model predicts neoantigen-frequency patterns and matches cohort data", "what_it_does_not_show": "Model fit can be nonidentifying; no intervention; shared public datasets", "confounders_present": [ "Model fit can be nonidentifying; no intervention; shared public datasets" ], "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": "39521615", "title": "Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression.", "citation": "Roerden M, Castro AB, Cui Y et al. Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression. Journal for immunotherapy of cancer. 2024.", "doi": "10.1136/jitc-2024-010249", "pmcid": "PMC11552027", "url": "https://pubmed.ncbi.nlm.nih.gov/39521615/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39521615/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39521615", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Defined-antigen mouse lung cancer plus clinical data", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Antigen concurrency/clonality shapes priming competition and therapy resistance; vaccination can restore control", "what_it_does_not_show": "Engineered antigen architectures and treatment; no mandatory human natural-history phases", "confounders_present": [ "Engineered antigen architectures and treatment; no mandatory human natural-history phases" ], "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": "32461698", "title": "Geospatial immune variability illuminates differential evolution of lung adenocarcinoma.", "citation": "AbdulJabbar K, Raza SEA, Rosenthal R et al. Geospatial immune variability illuminates differential evolution of lung adenocarcinoma. Nature medicine. 2020.", "doi": "10.1038/s41591-020-0900-x", "pmcid": "PMC7610840", "url": "https://pubmed.ncbi.nlm.nih.gov/32461698/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32461698/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32461698", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "TRACERx 100 patients and independent 970-patient lung cohort", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Immune-cold spatial regions associate with evolution and relapse", "what_it_does_not_show": "Geometry/immune associations; shared TRACERx and no immune intervention", "confounders_present": [ "Geometry/immune associations; shared TRACERx and no immune intervention" ], "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": [ "Shared TRACERx cohort/platform; distinct assay or analysis is not independent population replication." ] }, { "n": 28, "pmid": "31768072", "title": "Lack of detectable neoantigen depletion signals in the untreated cancer genome.", "citation": "Van den Eynden J, Jiménez-Sánchez A, Miller ML et al. Lack of detectable neoantigen depletion signals in the untreated cancer genome. Nature genetics. 2019.", "doi": "10.1038/s41588-019-0532-6", "pmcid": "PMC6887557", "url": "https://pubmed.ncbi.nlm.nih.gov/31768072/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31768072/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31768072", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph4, 0:Results:paragraph13, 0:Results:paragraph14, 0:Results:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Untreated human cancer genomes with matched simulated mutations", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Apparent depletion is reproduced by context-matched null mutations and diminishes after correction", "what_it_does_not_show": "Weak detectable depletion does not exclude editing via presentation loss, low power or early escape", "confounders_present": [ "Weak detectable depletion does not exclude editing via presentation loss, low power or early escape" ], "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": "31345234", "title": "Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes.", "citation": "Castro A, Ozturk K, Pyke RM et al. Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes. BMC medical genomics. 2019.", "doi": "10.1186/s12920-019-0544-1", "pmcid": "PMC6657029", "url": "https://pubmed.ncbi.nlm.nih.gov/31345234/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31345234/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31345234", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "TCGA HLA/B2M mutation analyses", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Presentation-defective tumors carry more mutation/neoantigen burden", "what_it_does_not_show": "Association and timing inference; no restored immune recognition or universal sequence", "confounders_present": [ "Association and timing inference; no restored immune recognition or universal sequence" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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": [ "SC2", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Primary chemical carcinogenesis in mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Abstract reports prolonged immune-controlled occult transformed cells and edited spontaneous escape", "what_it_does_not_show": "Full body unavailable in this examination; no animal-level depletion/spontaneous-frequency audit; phases can act independently", "confounders_present": [ "Full body unavailable in this examination; no animal-level depletion/spontaneous-frequency audit; phases can act independently" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22318521", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph2, 2:Main text:paragraph6, 2:Main text:paragraph7, 2:Main text:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Rag2-deficient MCA sarcomas transplanted into WT or depleted hosts", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mutant spectrin-beta2 recognition, antigen restoration and mixed-clone tracking establish T-cell-dependent selection", "what_it_does_not_show": "Transplanted hypermutated mouse clones; not every untreated human tumor", "confounders_present": [ "Transplanted hypermutated mouse clones; not every untreated human tumor" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "DC-specific IFNAR1 deletion and bone-marrow chimeras", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "DC type-I IFN response is required for cross-priming and tumor rejection; NK/myeloid contrasts exclude broad effector attribution", "what_it_does_not_show": "Highly immunogenic challenge models; no universal initiation phases", "confounders_present": [ "Highly immunogenic challenge models; no universal initiation phases" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22318517", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph1, 3:Main text:paragraph5, 3:Main text:paragraph7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Autochthonous KRAS/p53 sarcomas with lentiviral model antigens", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "what_it_does_not_show": "Engineered antigens and RNA/reporter restoration; no universal endogenous neoantigen rescue across human tumors", "confounders_present": [ "Engineered antigens and RNA/reporter restoration; no universal endogenous neoantigen rescue across human tumors" ], "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": "21876033", "title": "Cancer immunoediting of the NK group 2D ligand H60a.", "citation": "O'Sullivan T, Dunn GP, Lacoursiere DY et al. Cancer immunoediting of the NK group 2D ligand H60a. Journal of immunology (Baltimore, Md. : 1950). 2011.", "doi": "10.4049/jimmunol.1100413", "pmcid": "PMC3178735", "url": "https://pubmed.ncbi.nlm.nih.gov/21876033/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21876033/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21876033", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "MCA sarcoma passaging in Rag2-deficient mice", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NK/NKG2D selects against H60a-high tumor cells even without adaptive lymphocytes", "what_it_does_not_show": "Innate ligand selection and transplantation; not obligate adaptive three phases", "confounders_present": [ "Innate ligand selection and transplantation; not obligate adaptive three phases" ], "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": "19196996", "title": "Perforin-mediated suppression of B-cell lymphoma.", "citation": "Bolitho P, Street SE, Westwood JA et al. Perforin-mediated suppression of B-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America. 2009.", "doi": "10.1073/pnas.0809008106", "pmcid": "PMC2650333", "url": "https://pubmed.ncbi.nlm.nih.gov/19196996/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19196996/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19196996", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Four genetic B-cell lymphoma models with perforin loss", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin protects in v-Abl/bcl2 but not aggressive Myc lymphoma, defining context dependence", "what_it_does_not_show": "Perforin spans innate/adaptive effectors; no general immune-null claim", "confounders_present": [ "Perforin spans innate/adaptive effectors; no general immune-null claim" ], "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": "35486454", "title": "Quantification of Neoantigen-Mediated Immunoediting in Cancer Evolution.", "citation": "Wu T, Wang G, Wang X et al. Quantification of Neoantigen-Mediated Immunoediting in Cancer Evolution. Cancer research. 2022.", "doi": "10.1158/0008-5472.CAN-21-3717", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35486454/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35486454/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35486454", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "Pan-cancer distribution-based genomic analysis", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Reported neoantigen-negative-selection metrics distinguish elimination and escape scores", "what_it_does_not_show": "Author labels are not observed phases; null-model dispute and gene-expression/prefiltering biases remain", "confounders_present": [ "Author labels are not observed phases; null-model dispute and gene-expression/prefiltering biases remain" ], "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": 37, "pmid": "33953401", "title": "Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.", "citation": "Griffin GK, Wu J, Iracheta-Vellve A et al. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature. 2021.", "doi": "10.1038/s41586-021-03520-4", "pmcid": "PMC9166167", "url": "https://pubmed.ncbi.nlm.nih.gov/33953401/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33953401/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33953401", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph18, 1:Results:paragraph22. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "In vivo chromatin screens in LLC/B16 plus immunopeptidomics", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "SETDB1 loss derepresses TE antigens and treatment sensitivity requires MHC-I/CD8 cells", "what_it_does_not_show": "Untreated loss has little effect in tested models; no broad untreated necessary escape mechanism", "confounders_present": [ "Untreated loss has little effect in tested models; no broad untreated necessary escape 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": 38, "pmid": "34671158", "title": "KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements.", "citation": "Zhang SM, Cai WL, Liu X et al. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements. Nature. 2021.", "doi": "10.1038/s41586-021-03994-2", "pmcid": "PMC8555464", "url": "https://pubmed.ncbi.nlm.nih.gov/34671158/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34671158/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34671158", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Mouse melanoma KDM5B depletion", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "KDM5B recruits SETDB1 independently of demethylation; retroelements activate innate sensing and rejection", "what_it_does_not_show": "Specific melanoma machinery, pleiotropy and multiple antigen/sensing effects", "confounders_present": [ "Specific melanoma machinery, pleiotropy and multiple antigen/sensing 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": 39, "pmid": "28536458", "title": "Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma.", "citation": "Ritter C, Fan K, Paschen A et al. Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma. Scientific reports. 2017.", "doi": "10.1038/s41598-017-02608-0", "pmcid": "PMC5442125", "url": "https://pubmed.ncbi.nlm.nih.gov/28536458/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28536458/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28536458", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Merkel cell carcinoma lines and xenografts", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "HDAC inhibition and peptide provision restore HLA surface expression", "what_it_does_not_show": "APM restoration not coding neoantigen rescue; immunodeficient xenograft does not show functional host T-cell causality", "confounders_present": [ "APM restoration not coding neoantigen rescue; immunodeficient xenograft does not show functional host T-cell causality" ], "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": "33495232", "title": "Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis.", "citation": "Zhu M, Huang Y, Bender ME et al. Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis. Cancer research. 2021.", "doi": "10.1158/0008-5472.CAN-20-2808", "pmcid": "PMC8137539", "url": "https://pubmed.ncbi.nlm.nih.gov/33495232/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33495232/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33495232", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "SCLC preclinical ligand restoration and human expression", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Restoring NKG2D ligands suppresses growth/metastasis via NK cells", "what_it_does_not_show": "Lineage-linked innate avoidance; high TMB does not guarantee adaptive engagement", "confounders_present": [ "Lineage-linked innate avoidance; high TMB does not guarantee adaptive engagement" ], "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": "31564637", "title": "An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer.", "citation": "Burr ML, Sparbier CE, Chan KL et al. An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer cell. 2019.", "doi": "10.1016/j.ccell.2019.08.008", "pmcid": "PMC6876280", "url": "https://pubmed.ncbi.nlm.nih.gov/31564637/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31564637/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31564637", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "PRC2 CRISPR screens and developmental lineage models", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Conserved developmental PRC2 program silences antigen-presentation pathway and supports immune escape", "what_it_does_not_show": "Physiological lineage inheritance can precede selection; presentation silencing not necessarily antigen mutation loss", "confounders_present": [ "Physiological lineage inheritance can precede selection; presentation silencing not necessarily antigen mutation loss" ], "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": "12204534", "title": "Epigenetic changes in tumor Fas levels determine immune escape and response to therapy.", "citation": "Maecker HL, Yun Z, Maecker HT et al. Epigenetic changes in tumor Fas levels determine immune escape and response to therapy. Cancer cell. 2002.", "doi": "10.1016/s1535-6108(02)00095-8", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12204534/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12204534/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12204534", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Tumor Fas restoration/TSA treatment and host NK contrasts", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Fas rescue and host NK dependence restore tumor control/chemosensitivity", "what_it_does_not_show": "Fas susceptibility rather than neoantigen loss; scope-specific broad HDAC effects", "confounders_present": [ "Fas susceptibility rather than neoantigen loss; scope-specific broad HDAC 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": 43, "pmid": "36206767", "title": "Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas.", "citation": "Li Y, Goldberg EM, Chen X et al. Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas. Molecular cell. 2022.", "doi": "10.1016/j.molcel.2022.09.007", "pmcid": "PMC9588679", "url": "https://pubmed.ncbi.nlm.nih.gov/36206767/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36206767/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36206767", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "NSD1-mutant syngeneic and autochthonous head/neck models", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EZH2 inhibition restores immune infiltration and impairs mutant tumor growth despite retroelement expression", "what_it_does_not_show": "Viral mimicry is not always immunity; chromatin cross-talk context-dependent", "confounders_present": [ "Viral mimicry is not always immunity; chromatin cross-talk context-dependent" ], "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": "42102810", "title": "Whole-genome doubling drives immune evasion by silencing antigen presentation.", "citation": "Foidart P, Li Z, Cai X et al. Whole-genome doubling drives immune evasion by silencing antigen presentation. Cancer cell. 2026.", "doi": "10.1016/j.ccell.2026.04.007", "pmcid": "PMC13160227", "url": "https://pubmed.ncbi.nlm.nih.gov/42102810/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42102810/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42102810", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Cell-fusion-induced WGD mammary tumor models", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "WGD alters metabolism/chromatin and MHC regulation; PRC2 inhibition restores presentation and CD8 infiltration", "what_it_does_not_show": "Engineered WGD and many changes; no inference of obligatory prior equilibrium", "confounders_present": [ "Engineered WGD and many changes; no inference of obligatory prior equilibrium" ], "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": "10229818", "title": "Tumor antigens are constitutively presented in the draining lymph nodes.", "citation": "Marzo AL, Lake RA, Lo D et al. Tumor antigens are constitutively presented in the draining lymph nodes. Journal of immunology (Baltimore, Md. : 1950). 1999.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10229818/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10229818/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10229818", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "HA-expressing tumors with transferred naive TCR cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Antigen is continuously presented in draining nodes despite absence of strong CTL control", "what_it_does_not_show": "Proliferative priming is not elimination; engineered TCR/antigen and inoculation model", "confounders_present": [ "Proliferative priming is not elimination; engineered TCR/antigen and inoculation model" ], "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": "38581685", "title": "Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.", "citation": "Enfield KSS, Colliver E, Lee C et al. Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer. Cancer discovery. 2024.", "doi": "10.1158/2159-8290.CD-23-1380", "pmcid": "PMC11145179", "url": "https://pubmed.ncbi.nlm.nih.gov/38581685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38581685/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38581685", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "198 samples from 81 untreated TRACERx patients", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Neutrophil, fibroblast and vascular spatial barriers associate with metastasis and immune exclusion", "what_it_does_not_show": "Shared cohort; mechanistic hypotheses rather than intervention or traced first phase", "confounders_present": [ "Shared cohort; mechanistic hypotheses rather than intervention or traced first phase" ], "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": [ "Shared TRACERx cohort/platform; distinct assay or analysis is not independent population replication." ] }, { "n": 47, "pmid": "2945891", "title": "Highly malignant tumor variants retain tumor-specific antigens recognized by T helper cells.", "citation": "Van Waes C, Urban JL, Rothstein JL et al. Highly malignant tumor variants retain tumor-specific antigens recognized by T helper cells. The Journal of experimental medicine. 1986.", "doi": "10.1084/jem.164.5.1547", "pmcid": "PMC2188458", "url": "https://pubmed.ncbi.nlm.nih.gov/2945891/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/2945891/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID2945891", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Regressor/progressor mouse tumor variants", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Malignant variants retain helper-T-cell antigens while losing CTL targets; immunization discriminates protection", "what_it_does_not_show": "Specific antigen classes; retained antigens do not refute all immune selection", "confounders_present": [ "Specific antigen classes; retained antigens do not refute all immune selection" ], "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": "31685621", "title": "Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens.", "citation": "Linette GP, Becker-Hapak M, Skidmore ZL et al. Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1906026116", "pmcid": "PMC6876217", "url": "https://pubmed.ncbi.nlm.nih.gov/31685621/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31685621/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31685621", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Four metastatic melanoma patients with TCR functional validation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Expressed shared neoantigens can lack reactive clones; vaccination broadens responses", "what_it_does_not_show": "Small metastatic series and vaccination; ignorance is contextual not universal absence of immunity", "confounders_present": [ "Small metastatic series and vaccination; ignorance is contextual not universal absence of immunity" ], "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": "27433843", "title": "Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.", "citation": "Zaretsky JM, Garcia-Diaz A, Shin DS et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. The New England journal of medicine. 2016.", "doi": "10.1056/NEJMoa1604958", "pmcid": "PMC5007206", "url": "https://pubmed.ncbi.nlm.nih.gov/27433843/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27433843/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27433843", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Four paired anti-PD1 baseline/relapse melanomas", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "JAK1/JAK2/B2M alterations accompany acquired resistance and functional signaling/presentation defects", "what_it_does_not_show": "Exogenous checkpoint pressure; acquired resistance cannot prove untreated tumor initiation", "confounders_present": [ "Exogenous checkpoint pressure; acquired resistance cannot prove untreated tumor initiation" ], "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": "25294904", "title": "Genetic evolution of T-cell resistance in the course of melanoma progression.", "citation": "Sucker A, Zhao F, Real B et al. Genetic evolution of T-cell resistance in the course of melanoma progression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014.", "doi": "10.1158/1078-0432.CCR-14-0567", "pmcid": "PMC8728890", "url": "https://pubmed.ncbi.nlm.nih.gov/25294904/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25294904/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25294904", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Serial metastatic melanomas and autologous T-cell recognition", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Early B2M allele loss plus later second hit tracks progressive loss of recognition", "what_it_does_not_show": "Few lesions and established metastatic course; no mandatory equilibrium", "confounders_present": [ "Few lesions and established metastatic course; no mandatory equilibrium" ], "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": "29070816", "title": "Resistance to checkpoint blockade therapy through inactivation of antigen presentation.", "citation": "Sade-Feldman M, Jiao YJ, Chen JH et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nature communications. 2017.", "doi": "10.1038/s41467-017-01062-w", "pmcid": "PMC5656607", "url": "https://pubmed.ncbi.nlm.nih.gov/29070816/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29070816/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29070816", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "17 longitudinal checkpoint-treated melanomas plus validation cohorts", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "B2M defects enrich in progression/nonresponders and predict poor outcome", "what_it_does_not_show": "Treatment and observational enrichment; presenter loss rather than antigen mutation depletion", "confounders_present": [ "Treatment and observational enrichment; presenter loss rather than antigen mutation 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": 52, "pmid": "27642636", "title": "Lack of immunoediting in murine pancreatic cancer reversed with neoantigen.", "citation": "Evans RA, Diamond MS, Rech AJ et al. Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI insight. 2016.", "doi": "10.1172/jci.insight.88328", "pmcid": "PMC5026128", "url": "https://pubmed.ncbi.nlm.nih.gov/27642636/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27642636/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27642636", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph57, 0:Publisher HTML paragraphs:paragraph62, 0:Publisher HTML paragraphs:paragraph67, 0:Publisher HTML paragraphs:paragraph73, 0:Publisher HTML paragraphs:paragraph86, 0:Publisher HTML paragraphs:paragraph88. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "Autochthonous low-antigen KPC pancreatic model plus OVA challenge", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Juvenile sustained validated T-cell depletion leaves spontaneous tumor timing/survival intact; OVA addition restores CD8 rejection and selection", "what_it_does_not_show": "Scoped murine counterexample; predicted neoepitope absence not all possible antigens; OVA engineered positive control", "confounders_present": [ "Scoped murine counterexample; predicted neoepitope absence not all possible antigens; OVA engineered positive control" ], "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": 53, "pmid": "42276071", "title": "Immunoediting restricts clonal neoantigens in primary, treatment-naive human tumors.", "citation": "Borden ES, Castellano D, Kantzos EA et al. Immunoediting restricts clonal neoantigens in primary, treatment-naive human tumors. Immunity. 2026.", "doi": "10.1016/j.immuni.2026.05.005", "pmcid": "PMC13428410", "url": "https://pubmed.ncbi.nlm.nih.gov/42276071/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42276071/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42276071", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS::paragraph3, 1:RESULTS::paragraph7, 1:RESULTS::paragraph10, 1:RESULTS::paragraph13, 1:RESULTS::paragraph20. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Primary treatment-naive cSCC from immune-intact and suppressed patients", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "High-infiltrate intact-host tumors restrict strong-binding/immunogenic neoantigens to lower clonal frequency with purity/growth controls", "what_it_does_not_show": "Cross-sectional immunosuppression and age differences; not every cancer, not functional destruction of each predicted epitope", "confounders_present": [ "Cross-sectional immunosuppression and age differences; not every cancer, not functional destruction of each predicted epitope" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Perforin/p53-deficient spontaneous lymphoma mice", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin loss predisposes lymphoma and CD8 rejection differs strongly", "what_it_does_not_show": "Lymphoma-specific; p53 sarcoma incidence/onset unaffected; innate/adaptive substrate not separated globally", "confounders_present": [ "Lymphoma-specific; p53 sarcoma incidence/onset unaffected; innate/adaptive substrate not separated globally" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Her2/neu mammary tumors with perforin/NK/CD8 contrasts", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Perforin/NK reduces tumor number and delays onset without survival gain; CD8 depletion does not reproduce effect", "what_it_does_not_show": "Positive narrow innate surveillance cannot upgrade universal adaptive elimination", "confounders_present": [ "Positive narrow innate surveillance cannot upgrade universal adaptive 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": 56, "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": "2026-10-09", "status_checked_on": "2026-10-09", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Cytokine/perforin deficient aging mouse strains", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "IFNgamma/perforin restrain lymphoma and some late epithelial cancers", "what_it_does_not_show": "Strain-specific protection; IL12/18/TNF single loss not sufficient; broad pathways", "confounders_present": [ "Strain-specific protection; IL12/18/TNF single loss not sufficient; broad pathways" ], "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": "12093876", "title": "A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas.", "citation": "Crowe NY, Smyth MJ, Godfrey DI et al. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. The Journal of experimental medicine. 2002.", "doi": "10.1084/jem.20020092", "pmcid": "PMC2194015", "url": "https://pubmed.ncbi.nlm.nih.gov/12093876/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12093876/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12093876", "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": "MCA sarcoma with NKT transfer and defined effector defects", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Physiological NKT transfer protection requires CD1d, downstream NK/CD8, IFNgamma and perforin", "what_it_does_not_show": "Specific carcinogen challenge and pathway; NKT is not proof of general conventional-T sequence", "confounders_present": [ "Specific carcinogen challenge and pathway; NKT is not proof of general conventional-T sequence" ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "Perforin/beta2m deficient spontaneous lymphoma and transplant tests", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NK and gamma-delta effectors protect/reject tumors without conventional MHC-I context", "what_it_does_not_show": "Complex beta2m affects MHC/CD1d/CD16; no isolated adaptive obligatory phase", "confounders_present": [ "Complex beta2m affects MHC/CD1d/CD16; no isolated adaptive obligatory phase" ], "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": "11805143", "title": "Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development.", "citation": "Takeda K, Smyth MJ, Cretney E et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. The Journal of experimental medicine. 2002.", "doi": "10.1084/jem.20011171", "pmcid": "PMC2193611", "url": "https://pubmed.ncbi.nlm.nih.gov/11805143/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11805143/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11805143", "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": "MCA and p53-haploinsufficient tumors with TRAIL neutralization", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TRAIL blockade increases susceptible tumors and interacts with NK/IFNgamma", "what_it_does_not_show": "Specific effectors and susceptible lineages; no cross-etiology necessity", "confounders_present": [ "Specific effectors and susceptible lineages; no cross-etiology 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": 60, "pmid": "22927549", "title": "Cancer immunoediting by the innate immune system in the absence of adaptive immunity.", "citation": "O'Sullivan T, Saddawi-Konefka R, Vermi W et al. Cancer immunoediting by the innate immune system in the absence of adaptive immunity. The Journal of experimental medicine. 2012.", "doi": "10.1084/jem.20112738", "pmcid": "PMC3457735", "url": "https://pubmed.ncbi.nlm.nih.gov/22927549/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22927549/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22927549", "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", "SC4", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "WT, Rag2-null and Rag2/common-gamma-chain-null MCA models", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NK IFNgamma and M1 macrophages edit tumors without adaptive immunity; CD40 restores editing", "what_it_does_not_show": "Innate editing refutes an exclusively adaptive definition but remains carcinogen-model scoped", "confounders_present": [ "Innate editing refutes an exclusively adaptive definition but remains carcinogen-model scoped" ], "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": 61, "pmid": "31243362", "title": "Immune evasion before tumour invasion in early lung squamous carcinogenesis.", "citation": "Mascaux C, Angelova M, Vasaturo A et al. Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature. 2019.", "doi": "10.1038/s41586-019-1330-0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31243362/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31243362/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31243362", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "122 biopsies from 77 patients spanning nine lung lesion stages", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Immune activation and escape markers arise before invasion", "what_it_does_not_show": "Morphological trajectories and biomarkers rather than experimentally identified universal equilibrium", "confounders_present": [ "Morphological trajectories and biomarkers rather than experimentally identified universal equilibrium" ], "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": 62, "pmid": "32708311", "title": "Immune Escape Is an Early Event in Pre-Invasive Lesions of Lung Squamous Cell Carcinoma.", "citation": "Laville D, Casteillo F, Yvorel V et al. Immune Escape Is an Early Event in Pre-Invasive Lesions of Lung Squamous Cell Carcinoma. Diagnostics (Basel, Switzerland). 2020.", "doi": "10.3390/diagnostics10070503", "pmcid": "PMC7399898", "url": "https://pubmed.ncbi.nlm.nih.gov/32708311/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32708311/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32708311", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "24 bronchial dysplasia patients with normal/metaplastic controls", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "PD-L1 is present in a subset of dysplasias and absent in controls", "what_it_does_not_show": "PD-L1 staining not functional immune escape or phase sequence", "confounders_present": [ "PD-L1 staining not functional immune escape or phase sequence" ], "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": 63, "pmid": "42446924", "title": "IL-1α Expands SLC2A1highSPP1highIFNlow Myeloid Cells to Drive Immune Escape and Malignant Transformation of Precancers.", "citation": "Taner H, Gong W, Lanzel EA et al. IL-1α Expands SLC2A1highSPP1highIFNlow Myeloid Cells to Drive Immune Escape and Malignant Transformation of Precancers. Cancer research. 2026.", "doi": "10.1158/0008-5472.CAN-25-4416", "pmcid": "PMC13543150", "url": "https://pubmed.ncbi.nlm.nih.gov/42446924/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42446924/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42446924", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "Autochthonous oral Sox2-amplified precancer model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Early pharmacologic/genetic IL1 interruption reduces suppressive myeloid subsets, progression and mortality", "what_it_does_not_show": "Defined myeloid pre-emption model; no lineage proof that no brief equilibrium ever occurred", "confounders_present": [ "Defined myeloid pre-emption model; no lineage proof that no brief equilibrium ever occurred" ], "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": 70, "verified": 70, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC5", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistically plausible cell culture or transplantation-linked models without endogenous in vivo dependency cap at Γ.", "specific_trigger": "Aza restores DuPage reporter antigen expression; Rosenthal methylation associates with non-expression (PMID22318517,30894752). A naturally silenced mutant human locus with presentation/recognition rescue is not established by the examined passages. SETDB1 TE-antigen/MHC/CD8 epistasis under therapy is a distinct broader mechanism (PMID33953401). Exact SC5 stays Γ.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC6", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Association-only cancer claims cap at Β.", "specific_trigger": "No all-etiology human inception study identifies the obligatory sequence. Sustained validated juvenile T-cell depletion leaves KPC onset/survival intact, with OVA positive control (PMID27642636); early CRC escape and innate editing delimit phase generalization (PMID41193656,22927549). Human universal sequence inference remains Β.", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "The immune system actively sculpts tumors, driving all developing tumors through an obligate sequence of elimination, equilibrium and escape while selecting immune-resistant variants.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Ζ for scoped elimination/presentation reflects matching convergent endogenous/functional classes; transplantation caps do not erase them. Those same sources cannot upgrade all-human phase order or the distinct mutant-locus reversible-rescue endpoint. Negative contrasts never enter positive-causality tallies.", "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- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID31645760, PMID11323675, PMID21930769, PMID22318517, PMID12093876", "gamma_hard_rules_triggered": [ "Engineered antigen/TCR challenge demonstrates scoped capacity, not naturally obligatory phases.", "Transplantation and checkpoint-acquired resistance differ from untreated autochthonous initiation.", "HLA LOH removes a presenter rather than the antigen-bearing coding mutation.", "Methylation association and reporter re-expression require a separate immune-recognition rescue.", "Broad immune defects require antigen-specific and cell-restricted controls." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Lymphocyte/IFNgamma loss, DC-specific IFNAR1 deletion, antigen tolerance and effector transfer change tumor emergence/rejection (PMID11323675,21930769,22318517,12093876). Orthogonal contrasts support Ζ in specified etiologies. Perforin-insensitive Myc lymphoma and KPC outgrowth prevent universal Η.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID18026089", "gamma_hard_rules_triggered": [ "Engineered antigen/TCR challenge demonstrates scoped capacity, not naturally obligatory phases.", "Transplantation and checkpoint-acquired resistance differ from untreated autochthonous initiation.", "HLA LOH removes a presenter rather than the antigen-bearing coding mutation.", "Methylation association and reporter re-expression require a separate immune-recognition rescue.", "Broad immune defects require antigen-specific and cell-restricted controls." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Koebel reports transformed occult cells under prolonged immune restraint and later edited spontaneous escape in chemical carcinogenesis (PMID18026089), supporting Δ within that model. Only its complete primary abstract was accessible; exact body/supplement intervention frequencies remain unverified. Therapeutic CTL-induced arrest (PMID25127875) is not independent spontaneous equilibrium.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID22318521, PMID22318517", "gamma_hard_rules_triggered": [ "Engineered antigen/TCR challenge demonstrates scoped capacity, not naturally obligatory phases.", "Transplantation and checkpoint-acquired resistance differ from untreated autochthonous initiation.", "HLA LOH removes a presenter rather than the antigen-bearing coding mutation.", "Methylation association and reporter re-expression require a separate immune-recognition rescue.", "Broad immune defects require antigen-specific and cell-restricted controls." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Matsushita tracks selection of pre-existing mutant-spectrin-negative clones and restores antigen-dependent rejection (PMID22318521). Treatment-naive 2026 cSCC adds clonal restriction with purity/growth and HLA controls (PMID42276071). Context-matched nulls undermine uncorrected pan-cancer depletion (PMID31768072). This supports Ε in mapped antigen/clonal contexts, not all untreated tumors.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID40614739, PMID22318517, PMID25294904", "gamma_hard_rules_triggered": [ "Engineered antigen/TCR challenge demonstrates scoped capacity, not naturally obligatory phases.", "Transplantation and checkpoint-acquired resistance differ from untreated autochthonous initiation.", "HLA LOH removes a presenter rather than the antigen-bearing coding mutation.", "Methylation association and reporter re-expression require a separate immune-recognition rescue.", "Broad immune defects require antigen-specific and cell-restricted controls." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Autochthonous model-antigen/MHC contrasts, serial human autologous recognition/B2M loss, clonal organoid–TIL assays and allele-specific HLA evolution converge (PMID22318517,25294904,40614739,29107330). Defined presentation escape reaches Ζ. Not every HLA event is functionally restored or isolated from passenger CIN.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Engineered antigen/TCR challenge demonstrates scoped capacity, not naturally obligatory phases.", "Transplantation and checkpoint-acquired resistance differ from untreated autochthonous initiation.", "HLA LOH removes a presenter rather than the antigen-bearing coding mutation.", "Methylation association and reporter re-expression require a separate immune-recognition rescue.", "Broad immune defects require antigen-specific and cell-restricted controls." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Aza restores DuPage reporter antigen expression; Rosenthal methylation associates with non-expression (PMID22318517,30894752). A naturally silenced mutant human locus with presentation/recognition rescue is not established by the examined passages. SETDB1 TE-antigen/MHC/CD8 epistasis under therapy is a distinct broader mechanism (PMID33953401). Exact SC5 stays Γ.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC6", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Engineered antigen/TCR challenge demonstrates scoped capacity, not naturally obligatory phases.", "Transplantation and checkpoint-acquired resistance differ from untreated autochthonous initiation.", "HLA LOH removes a presenter rather than the antigen-bearing coding mutation.", "Methylation association and reporter re-expression require a separate immune-recognition rescue.", "Broad immune defects require antigen-specific and cell-restricted controls." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "No all-etiology human inception study identifies the obligatory sequence. Sustained validated juvenile T-cell depletion leaves KPC onset/survival intact, with OVA positive control (PMID27642636); early CRC escape and innate editing delimit phase generalization (PMID41193656,22927549). Human universal sequence inference remains Β.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[2] Both antigen-specific CD4 and CD8 responses contribute to rejection with local class-II antigen requirements", "[6] Lymphocytes and IFNgamma suppress tumors and select less immunogenic variants", "[32] DC type-I IFN response is required for cross-priming and tumor rejection; NK/myeloid contrasts exclude broad effector attribution", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[57] Physiological NKT transfer protection requires CD1d, downstream NK/CD8, IFNgamma and perforin" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[2] Both antigen-specific CD4 and CD8 responses contribute to rejection with local class-II antigen requirements", "[6] Lymphocytes and IFNgamma suppress tumors and select less immunogenic variants", "[32] DC type-I IFN response is required for cross-priming and tumor rejection; NK/myeloid contrasts exclude broad effector attribution", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[57] Physiological NKT transfer protection requires CD1d, downstream NK/CD8, IFNgamma and perforin" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[2] Both antigen-specific CD4 and CD8 responses contribute to rejection with local class-II antigen requirements", "[6] Lymphocytes and IFNgamma suppress tumors and select less immunogenic variants", "[32] DC type-I IFN response is required for cross-priming and tumor rejection; NK/myeloid contrasts exclude broad effector attribution", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[57] Physiological NKT transfer protection requires CD1d, downstream NK/CD8, IFNgamma and perforin" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "no", "supporting_evidence": [ "[2] Both antigen-specific CD4 and CD8 responses contribute to rejection with local class-II antigen requirements", "[6] Lymphocytes and IFNgamma suppress tumors and select less immunogenic variants", "[32] DC type-I IFN response is required for cross-priming and tumor rejection; NK/myeloid contrasts exclude broad effector attribution", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[57] Physiological NKT transfer protection requires CD1d, downstream NK/CD8, IFNgamma and perforin" ], "what_would_cross_it": "Prospectively replicate immune-specific loss/restoration across fixed etiologies without changing carcinogenesis or viability." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[30] Abstract reports prolonged immune-controlled occult transformed cells and edited spontaneous escape" ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "no", "supporting_evidence": [ "[30] Abstract reports prolonged immune-controlled occult transformed cells and edited spontaneous escape" ], "what_would_cross_it": "Independent lineage-confirmed occult persistence with delayed immune interruption/restoration; finish original methods/supplements." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[31] Mutant spectrin-beta2 recognition, antigen restoration and mixed-clone tracking establish T-cell-dependent selection", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression" ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[31] Mutant spectrin-beta2 recognition, antigen restoration and mixed-clone tracking establish T-cell-dependent selection", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression" ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "no", "supporting_evidence": [ "[31] Mutant spectrin-beta2 recognition, antigen restoration and mixed-clone tracking establish T-cell-dependent selection", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression" ], "what_would_cross_it": "Validate presented mutant epitopes and TCR recognition, use powered sequence-context nulls, and trace antigen-clone loss separately from presenter attrition." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[17] Functional immune evasion differs among subclones within each tumor", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[50] Early B2M allele loss plus later second hit tracks progressive loss of recognition" ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[17] Functional immune evasion differs among subclones within each tumor", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[50] Early B2M allele loss plus later second hit tracks progressive loss of recognition" ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[17] Functional immune evasion differs among subclones within each tumor", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[50] Early B2M allele loss plus later second hit tracks progressive loss of recognition" ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "no", "supporting_evidence": [ "[17] Functional immune evasion differs among subclones within each tumor", "[33] Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression", "[50] Early B2M allele loss plus later second hit tracks progressive loss of recognition" ], "what_would_cross_it": "Physiologically restore lost HLA alleles in matched clones; test autologous killing and tumor control with CIN passenger controls." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Selectively reverse endogenous mutant-antigen silencing, recover peptide presentation and recognition, then restore silence to reverse control." }, { "subclaim_id": "SC6", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Prospective untreated inception cohorts across predefined etiologies must trace all causal phase transitions and count bypasses." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "KPC juvenile sustained CD4/CD8 depletion, isotype and OVA positive control (PMID27642636).", "WT/mutant antigen rescue, Rag2 hosts, depletion and fluorescent-label controls (PMID22318521).", "Antigen tolerance, antigen-free vectors and delayed depletion (PMID22318517).", "Selection-free tri/pentanucleotide-matched mutation simulations (PMID31768072).", "Borden retained HLA, purity/growth adjustment and immune-host strata (PMID42276071).", "SETDB1 untreated versus therapy and B2m/CD8 epistasis (PMID33953401)." ], "note": "Predefined low-antigen, carcinogen, lymphoma, epithelial and treatment contexts map boundaries. KPC, Myc/perforin negatives, innate-only editing and early CRC escape do not erase selected-model immune causality. They prevent universal adaptive sequence inference. Shared TRACERx/TCGA data are not independent population replications." }, "falsification_patterns_met": [ { "pattern": "Perturbing the proposed feature leaves the claimed output intact", "evidence": "KPC verified sustained T-cell depletion leaves onset/survival intact with OVA positive control (PMID27642636). Scoped contradiction of universal adaptive necessity.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Phase labels reified", "where": "Scores/morphological stages do not observe the same clone traversing all phases." }, { "pitfall": "Presenter loss equals antigen loss", "where": "HLA/B2M and coding mutation depletion have different substrates." }, { "pitfall": "Treatment generalized to untreated initiation", "where": "Checkpoint-acquired JAK/B2M escape stays treatment-scoped." }, { "pitfall": "Shared cohorts treated as independence", "where": "TRACERx/TCGA repeatedly reuse data." }, { "pitfall": "Provider substitution/date accepted", "where": "Consensus Borden date error and Wu preprint were corrected with journal records." } ], "causal_tally_audit": { "tally_claimed_by_document": 7, "tally_after_audit": 7, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts/platforms and multiple outcomes do not constitute independent causal lines." ] }, "steelman": { "case_one_rung_higher": "One rung higher, Γ: classical mouse phases, engineered autochthonous antigens and human lesion/genomic trajectories make the expansive sequence mechanistically conceivable.", "case_one_rung_lower": "One rung lower, Α: the whole account is a narrative without meaningful evidence. That misses experimentally demonstrated selected-phase causality.", "which_rejected": "Reject Α because real antigen-dependent selection and occult restraint exist. Reject Γ for the exact every-human obligatory gate because model-specific plausibility does not identify that scope and faces endogenous counterexamples. Keep Ζ for matching narrow functions.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Prospectively barcode autochthonous clones across predefined high/low-antigen etiologies; serially trace immune contact, viable occult persistence and outgrowth with delayed antigen-specific interruption and physiological restoration; pair with untreated human surveillance." }, "final_score": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "Moderate reflects evidence density and reproducibility, not the reviewer's access depth and not any belief about correctness: the registered universal-scope subclaim has no replicated human inception dataset, the human genomic evidence repeatedly reuses the TRACERx and TCGA cohorts, and controls are heterogeneous across etiologies and effector pathways.", "rests_on_non_peer_reviewed_work": false, "rationale": "SC6 gates the registered universal scope and remains Β. Human phase histories are chiefly inferred from sampled lesions/genomes without an all-etiology causal inception dataset. This does not cap scoped immune elimination or presentation escape, which reach Ζ through matching genetic and functional contrasts. Low-antigen KPC, innate-only editing and early evasion delimit the universal inference." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Immune pressure can restrain and sculpt already transformed variants; upstream oncogenic and baseline antigen/lineage context remains. All-human initiation necessity plus sufficiency is not shown, so steps 3/4 do not license universal primary-driver status. This role applies to supported scoped selection.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named artifacts are completed mechanistic and boundary studies, not experiments now in progress: 2025 timed-antigen and CRC epigenomic work plus the 2026 treatment-naive cSCC and IL1 precancer studies. No experiment addressing the SC6 boundary check (a prospective untreated all-etiology inception cohort tracing phase transitions) was identified as underway, and no unnamed pending trial is claimed.", "justification": "The named artifacts are completed mechanistic and boundary studies, not experiments now in progress: 2025 timed-antigen and CRC epigenomic work plus the 2026 treatment-naive cSCC and IL1 precancer studies. No experiment addressing the SC6 boundary check (a prospective untreated all-etiology inception cohort tracing phase transitions) was identified as underway, and no unnamed pending trial is claimed." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to move the grade imminently.", "justification": "No named pending result is asserted to move the grade imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Β", "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": "Β", "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 barcode autochthonous clones across predefined high/low-antigen etiologies; serially trace immune contact, viable occult persistence and outgrowth with delayed antigen-specific interruption and physiological restoration; pair with untreated human surveillance.", "readout": "Clone survival, occult proliferation balance, antigen/presenter substrate, autologous recognition and tumor outcomes", "critical_control": "Antigen-negative lineages, tolerant/depleted/intact hosts, restoration, CIN-matched HLA passengers, mutation-signature nulls and blinded phase labels", "supporting_result": "Every predefined developing clone traverses causally verified sequential phases with matching interruption/restoration effects", "falsifying_result": "Tracked clones bypass the required adaptive phase or inherit early escape without preceding causal equilibrium" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Trace phases within the same untreated clone.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Prespecify antigen/etiology scope and count bypasses.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Replicate and fully audit occult-equilibrium experiments.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Validate presented epitopes and TCR recognition beyond predictions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Control sequence context, purity, growth and detection power.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Restore HLA with matched CIN passenger controls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Reverse endogenous mutant-antigen methylation with functional recognition rescue.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Track early myeloid pre-emption versus brief equilibrium.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Separate innate ligand editing and retained helper antigens.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 10", "statement": "Audit errata, inaccessible bodies and supplements before complete-paper publication claims.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "63 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "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": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Immune genetics, antigen tolerance/rescue, cell-restricted pathways, functional patient assays and host immunosuppression are live upper-ladder routes without RCT-only requirements. They strengthen narrow claims while universal phase order and endogenous mutant-locus rescue retain separate missing endpoints." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Immune genetics, antigen tolerance/rescue, cell-restricted pathways, functional patient assays and host immunosuppression are live upper-ladder routes without RCT-only requirements. They strengthen narrow claims while universal phase order and endogenous mutant-locus rescue retain separate missing endpoints." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Immune genetics, antigen tolerance/rescue, cell-restricted pathways, functional patient assays and host immunosuppression are live upper-ladder routes without RCT-only requirements. They strengthen narrow claims while universal phase order and endogenous mutant-locus rescue retain separate missing endpoints." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Immune genetics, antigen tolerance/rescue, cell-restricted pathways, functional patient assays and host immunosuppression are live upper-ladder routes without RCT-only requirements. They strengthen narrow claims while universal phase order and endogenous mutant-locus rescue retain separate missing endpoints." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Immune genetics, antigen tolerance/rescue, cell-restricted pathways, functional patient assays and host immunosuppression are live upper-ladder routes without RCT-only requirements. They strengthen narrow claims while universal phase order and endogenous mutant-locus rescue retain separate missing endpoints." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 63, "claims_total": 70, "claims_verified": 70, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 63, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Tumor TIM3 perturbation links stemness, suppressive gamma-delta cells and metastatic seeding Metastatic context and multifunctional signaling; no obligatory inception sequence", "carries_number": true, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "Both antigen-specific CD4 and CD8 responses contribute to rejection with local class-II antigen requirements Scoped antigens and models; not all human tumors", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "High-quality neoantigen loss and clonal fitness model support selection in long survivors Survivor selection and recurrence; inference rather than experimental untreated initiation", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "NKG2D ligand recognition restrains naturally arising B-cell tumors Innate pathway; grade-dependent human association not universal adaptive sequence", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "Multiregional HLA loss and TCR patterns accompany lethal metastatic evolution Heavily treated endpoint sampling; no untreated inception or phase causality", "carries_number": false, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C6", "text": "Lymphocytes and IFNgamma suppress tumors and select less immunogenic variants Broad immune deficiency and specific etiologies; every tumor sequence not established", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "IFNgamma neutralization reverses growth arrest; arrest can dominate lysis Adoptive therapy and differing IFNgamma sensitivity; not spontaneous occult equilibrium", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "Tumor glucose competition can override T-cell protection and impair effector function Metabolic suppression permits antigen-retaining escape; engineered pathway sufficiency", "carries_number": false, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C9", "text": "Mutant-antigen-specific T cells reactivate and vaccination rejects tumors Therapeutically augmented rejection; not untreated universal selection", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "Host hematopoietic IFN responses protect against primary and transplanted tumors Broad pathway; linked erratum notice lacks resolved PMID/details", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "Endothelial responsiveness is necessary and sufficient for induced ischemic regression Induced IFNgamma in established tumors; not nascent elimination or equilibrium", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "Immune context associates with copy-number antigen loss, HLA dysfunction and neoantigen promoter methylation Shared TRACERx; methylation association does not demonstrate demethylation/recognition rescue", "carries_number": false, "load_bearing_for": [ "SC3", "SC4", "SC5", "SC6" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph13, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "Empirical sequence analyses suggest negative selection in immune-exposed regions Null mutation context, expression and prediction biases matter; no immune intervention", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C14", "text": "MHC genotype presentation scores predict mutation probabilities Computational association; genotype and mutation processes may confound selection", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "Allele-specific HLA loss is focal, often subclonal, and linked to lost-allele-binding neoantigens Loss of presenter does not delete antigen mutation; cohort overlap and CIN passenger alternatives", "carries_number": false, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph29, 1:Results:paragraph30, 1:Results:paragraph65. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C16", "text": "HLA repression/splicing and LOH refine effective neoantigen burden and metastasis associations Shared cohorts and transcriptomic disruption; not universal sequence or functional restoration", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "Functional immune evasion differs among subclones within each tumor Ex vivo propagation and three patients; linked 2026 correction details not audited", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C18", "text": "Myeloid deletion reduces tumor formation with stromal T-cell activation and residual escape Inflammatory carcinogenesis and pleiotropy; adaptive mechanism inferred partly from transplantation", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C19", "text": "Spatial macrophage SIGLEC10/CD52 axis associates with repair context Spatial multiomics generates mechanism candidates; no obligatory sequence or definitive causal editing", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C20", "text": "Germline epitope burden associates with amplified subtype incidence and cold aggressive tumors Germline selection inference; no prospective phase transitions", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C21", "text": "Spatial immune context and inferred subclone fitness vary along tumors Retrospective inferred editing and expression; not phase necessity", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "Chromatin changes, antigen silencing and exclusion are inferred near transformation with little later editing Timing inferred from sampled extant lesions; early escape contradicts assuming a long mandatory equilibrium", "carries_number": false, "load_bearing_for": [ "SC5", "SC6" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "Timed antigen removal and T-cell/IFNgamma interruption separate direct and bystander early elimination Engineered antigens; antigen-negative cells also exist without T cells; silencing alone not sufficient", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC5" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C24", "text": "Editing estimates vary widely with method, neoantigen criteria and reference data Original method comparison not causal immune editing; union of estimates is not truth validation", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C25", "text": "Selection/escape model predicts neoantigen-frequency patterns and matches cohort data Model fit can be nonidentifying; no intervention; shared public datasets", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C26", "text": "Antigen concurrency/clonality shapes priming competition and therapy resistance; vaccination can restore control Engineered antigen architectures and treatment; no mandatory human natural-history phases", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "Immune-cold spatial regions associate with evolution and relapse Geometry/immune associations; shared TRACERx and no immune intervention", "carries_number": false, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C28", "text": "Apparent depletion is reproduced by context-matched null mutations and diminishes after correction Weak detectable depletion does not exclude editing via presentation loss, low power or early escape", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph4, 0:Results:paragraph13, 0:Results:paragraph14, 0:Results:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C29", "text": "Presentation-defective tumors carry more mutation/neoantigen burden Association and timing inference; no restored immune recognition or universal sequence", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C30", "text": "Abstract reports prolonged immune-controlled occult transformed cells and edited spontaneous escape Full body unavailable in this examination; no animal-level depletion/spontaneous-frequency audit; phases can act independently", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C31", "text": "Mutant spectrin-beta2 recognition, antigen restoration and mixed-clone tracking establish T-cell-dependent selection Transplanted hypermutated mouse clones; not every untreated human tumor", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph2, 2:Main text:paragraph6, 2:Main text:paragraph7, 2:Main text:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "DC type-I IFN response is required for cross-priming and tumor rejection; NK/myeloid contrasts exclude broad effector attribution Highly immunogenic challenge models; no universal initiation phases", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C33", "text": "Immune/tolerance contrasts and antigen or presentation loss establish selection; Aza restores reporter antigen expression Engineered antigens and RNA/reporter restoration; no universal endogenous neoantigen rescue across human tumors", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4", "SC5" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph1, 3:Main text:paragraph5, 3:Main text:paragraph7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "NK/NKG2D selects against H60a-high tumor cells even without adaptive lymphocytes Innate ligand selection and transplantation; not obligate adaptive three phases", "carries_number": true, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "Perforin protects in v-Abl/bcl2 but not aggressive Myc lymphoma, defining context dependence Perforin spans innate/adaptive effectors; no general immune-null claim", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C36", "text": "Reported neoantigen-negative-selection metrics distinguish elimination and escape scores Author labels are not observed phases; null-model dispute and gene-expression/prefiltering biases remain", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "SETDB1 loss derepresses TE antigens and treatment sensitivity requires MHC-I/CD8 cells Untreated loss has little effect in tested models; no broad untreated necessary escape mechanism", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph18, 1:Results:paragraph22. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C38", "text": "KDM5B recruits SETDB1 independently of demethylation; retroelements activate innate sensing and rejection Specific melanoma machinery, pleiotropy and multiple antigen/sensing effects", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "HDAC inhibition and peptide provision restore HLA surface expression APM restoration not coding neoantigen rescue; immunodeficient xenograft does not show functional host T-cell causality", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "Restoring NKG2D ligands suppresses growth/metastasis via NK cells Lineage-linked innate avoidance; high TMB does not guarantee adaptive engagement", "carries_number": true, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C41", "text": "Conserved developmental PRC2 program silences antigen-presentation pathway and supports immune escape Physiological lineage inheritance can precede selection; presentation silencing not necessarily antigen mutation loss", "carries_number": true, "load_bearing_for": [ "SC4", "SC5", "SC6" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Fas rescue and host NK dependence restore tumor control/chemosensitivity Fas susceptibility rather than neoantigen loss; scope-specific broad HDAC effects", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "EZH2 inhibition restores immune infiltration and impairs mutant tumor growth despite retroelement expression Viral mimicry is not always immunity; chromatin cross-talk context-dependent", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C44", "text": "WGD alters metabolism/chromatin and MHC regulation; PRC2 inhibition restores presentation and CD8 infiltration Engineered WGD and many changes; no inference of obligatory prior equilibrium", "carries_number": true, "load_bearing_for": [ "SC4", "SC5", "SC6" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C45", "text": "Antigen is continuously presented in draining nodes despite absence of strong CTL control Proliferative priming is not elimination; engineered TCR/antigen and inoculation model", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C46", "text": "Neutrophil, fibroblast and vascular spatial barriers associate with metastasis and immune exclusion Shared cohort; mechanistic hypotheses rather than intervention or traced first phase", "carries_number": false, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C47", "text": "Malignant variants retain helper-T-cell antigens while losing CTL targets; immunization discriminates protection Specific antigen classes; retained antigens do not refute all immune selection", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C48", "text": "Expressed shared neoantigens can lack reactive clones; vaccination broadens responses Small metastatic series and vaccination; ignorance is contextual not universal absence of immunity", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C49", "text": "JAK1/JAK2/B2M alterations accompany acquired resistance and functional signaling/presentation defects Exogenous checkpoint pressure; acquired resistance cannot prove untreated tumor initiation", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "Early B2M allele loss plus later second hit tracks progressive loss of recognition Few lesions and established metastatic course; no mandatory equilibrium", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "B2M defects enrich in progression/nonresponders and predict poor outcome Treatment and observational enrichment; presenter loss rather than antigen mutation depletion", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "Juvenile sustained validated T-cell depletion leaves spontaneous tumor timing/survival intact; OVA addition restores CD8 rejection and selection Scoped murine counterexample; predicted neoepitope absence not all possible antigens; OVA engineered positive control", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC6" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph57, 0:Publisher HTML paragraphs:paragraph62, 0:Publisher HTML paragraphs:paragraph67, 0:Publisher HTML paragraphs:paragraph73, 0:Publisher HTML paragraphs:paragraph86, 0:Publisher HTML paragraphs:paragraph88. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "High-infiltrate intact-host tumors restrict strong-binding/immunogenic neoantigens to lower clonal frequency with purity/growth controls Cross-sectional immunosuppression and age differences; not every cancer, not functional destruction of each predicted epitope", "carries_number": false, "load_bearing_for": [ "SC3", "SC6" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS::paragraph3, 1:RESULTS::paragraph7, 1:RESULTS::paragraph10, 1:RESULTS::paragraph13, 1:RESULTS::paragraph20. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C54", "text": "Perforin loss predisposes lymphoma and CD8 rejection differs strongly Lymphoma-specific; p53 sarcoma incidence/onset unaffected; innate/adaptive substrate not separated globally", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Perforin/NK reduces tumor number and delays onset without survival gain; CD8 depletion does not reproduce effect Positive narrow innate surveillance cannot upgrade universal adaptive elimination", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "IFNgamma/perforin restrain lymphoma and some late epithelial cancers Strain-specific protection; IL12/18/TNF single loss not sufficient; broad pathways", "carries_number": false, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "Physiological NKT transfer protection requires CD1d, downstream NK/CD8, IFNgamma and perforin Specific carcinogen challenge and pathway; NKT is not proof of general conventional-T sequence", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "NK and gamma-delta effectors protect/reject tumors without conventional MHC-I context Complex beta2m affects MHC/CD1d/CD16; no isolated adaptive obligatory phase", "carries_number": false, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "TRAIL blockade increases susceptible tumors and interacts with NK/IFNgamma Specific effectors and susceptible lineages; no cross-etiology necessity", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C60", "text": "NK IFNgamma and M1 macrophages edit tumors without adaptive immunity; CD40 restores editing Innate editing refutes an exclusively adaptive definition but remains carcinogen-model scoped", "carries_number": true, "load_bearing_for": [ "SC1", "SC4", "SC6" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C61", "text": "Immune activation and escape markers arise before invasion Morphological trajectories and biomarkers rather than experimentally identified universal equilibrium", "carries_number": false, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C62", "text": "PD-L1 is present in a subset of dysplasias and absent in controls PD-L1 staining not functional immune escape or phase sequence", "carries_number": true, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C63", "text": "Early pharmacologic/genetic IL1 interruption reduces suppressive myeloid subsets, progression and mortality Defined myeloid pre-emption model; no lineage proof that no brief equilibrium ever occurred", "carries_number": true, "load_bearing_for": [ "SC4", "SC6" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Lymphocyte/IFNgamma loss, DC-specific IFNAR1 deletion, antigen tolerance and effector transfer change tumor emergence/rejection (PMID11323675,21930769,22318517,12093876). Orthogonal contrasts support Ζ in specified etiologies. Perforin-insensitive Myc lymphoma and KPC outgrowth prevent universal Η.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 2, 4, 6, 9, 10, 11, 18, 23, 26, 31, 32, 33, 35, 52, 54, 55, 56, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Koebel reports transformed occult cells under prolonged immune restraint and later edited spontaneous escape in chemical carcinogenesis (PMID18026089), supporting Δ within that model. Only its complete primary abstract was accessible; exact body/supplement intervention frequencies remain unverified. Therapeutic CTL-induced arrest (PMID25127875) is not independent spontaneous equilibrium.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 7, 30, 45 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Matsushita tracks selection of pre-existing mutant-spectrin-negative clones and restores antigen-dependent rejection (PMID22318521). Treatment-naive 2026 cSCC adds clonal restriction with purity/growth and HLA controls (PMID42276071). Context-matched nulls undermine uncorrected pan-cancer depletion (PMID31768072). This supports Ε in mapped antigen/clonal contexts, not all untreated tumors.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 3, 6, 12, 13, 14, 20, 21, 23, 24, 25, 28, 29, 31, 33, 36, 47, 48, 52, 53 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC4", "text": "Autochthonous model-antigen/MHC contrasts, serial human autologous recognition/B2M loss, clonal organoid–TIL assays and allele-specific HLA evolution converge (PMID22318517,25294904,40614739,29107330). Defined presentation escape reaches Ζ. Not every HLA event is functionally restored or isolated from passenger CIN.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 5, 7, 8, 9, 11, 12, 15, 16, 17, 18, 19, 26, 27, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 46, 49, 50, 51, 60, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC5", "text": "Aza restores DuPage reporter antigen expression; Rosenthal methylation associates with non-expression (PMID22318517,30894752). A naturally silenced mutant human locus with presentation/recognition rescue is not established by the examined passages. SETDB1 TE-antigen/MHC/CD8 epistasis under therapy is a distinct broader mechanism (PMID33953401). Exact SC5 stays Γ.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 12, 22, 23, 33, 37, 38, 39, 41, 42, 43, 44 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC6", "text": "No all-etiology human inception study identifies the obligatory sequence. Sustained validated juvenile T-cell depletion leaves KPC onset/survival intact, with OVA positive control (PMID27642636); early CRC escape and innate editing delimit phase generalization (PMID41193656,22927549). Human universal sequence inference remains Β.", "carries_number": false, "load_bearing_for": [ "SC6" ], "source_ns": [ 1, 3, 4, 5, 8, 12, 14, 15, 20, 21, 22, 27, 28, 30, 34, 35, 36, 40, 41, 44, 45, 46, 47, 48, 52, 53, 54, 55, 56, 58, 60, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "Immune selection is causal in defined cancers; an obligatory elimination–equilibrium–escape sequence across every developing human tumor is unsupported.", "carries_number": false, "load_bearing_for": [ "SC6" ], "source_ns": [ 6, 30, 31, 33, 52, 28, 53, 22 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Rozalén C, Sangrador I, Avalle S et al. TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak. Cancer cell. 2025.", "tier": "A", "kind": "primary", "pmid": "40645187", "doi": "10.1016/j.ccell.2025.06.015", "url": "https://pubmed.ncbi.nlm.nih.gov/40645187/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40645187", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC4", "CSC6" ] }, { "n": 2, "citation": "Alspach E, Lussier DM, Miceli AP et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. 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Journal of immunology (Baltimore, Md. : 1950). 2016.", "tier": "A", "kind": "primary", "pmid": "27183590", "doi": "10.4049/jimmunol.1501982", "url": "https://pubmed.ncbi.nlm.nih.gov/27183590/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27183590", "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", "CSC6" ] }, { "n": 5, "citation": "De Mattos-Arruda L, Sammut SJ, Ross EM et al. The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. 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Cancer immunology research. 2015.", "tier": "A", "kind": "primary", "pmid": "25127875", "doi": "10.1158/2326-6066.CIR-14-0098", "url": "https://pubmed.ncbi.nlm.nih.gov/25127875/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25127875", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC2", "CSC4" ] }, { "n": 8, "citation": "Chang CH, Qiu J, O'Sullivan D et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015.", "tier": "A", "kind": "primary", "pmid": "26321679", "doi": "10.1016/j.cell.2015.08.016", "url": "https://pubmed.ncbi.nlm.nih.gov/26321679/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26321679", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC4", "CSC6" ] }, { "n": 9, "citation": "Gubin MM, Zhang X, Schuster H et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014.", "tier": "A", "kind": "primary", "pmid": "25428507", "doi": "10.1038/nature13988", "url": "https://pubmed.ncbi.nlm.nih.gov/25428507/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25428507", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC4" ] }, { "n": 10, "citation": "Dunn GP, Bruce AT, Sheehan KC et al. A critical function for type I interferons in cancer immunoediting. Nature immunology. 2005.", "tier": "A", "kind": "primary", "pmid": "15951814", "doi": "10.1038/ni1213", "url": "https://pubmed.ncbi.nlm.nih.gov/15951814/", "status_flags": [ "ErratumIn: PMID not supplied in the PubMed record" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15951814", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC1" ] }, { "n": 11, "citation": "Kammertoens T, Friese C, Arina A et al. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "28445461", "doi": "10.1038/nature22311", "url": "https://pubmed.ncbi.nlm.nih.gov/28445461/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28445461", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1", "CSC4" ] }, { "n": 12, "citation": "Rosenthal R, Cadieux EL, Salgado R et al. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019.", "tier": "A", "kind": "primary", "pmid": "30894752", "doi": "10.1038/s41586-019-1032-7", "url": "https://pubmed.ncbi.nlm.nih.gov/30894752/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30894752", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph13, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC3", "CSC4", "CSC5", "CSC6" ] }, { "n": 13, "citation": "Zapata L, Pich O, Serrano L et al. Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome. Genome biology. 2018.", "tier": "A", "kind": "primary", "pmid": "29855388", "doi": "10.1186/s13059-018-1434-0", "url": "https://pubmed.ncbi.nlm.nih.gov/29855388/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29855388", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC3" ] }, { "n": 14, "citation": "Beauchemin L, Slifker M, Rossell D et al. Characterizing MHC-I Genotype Predictive Power for Oncogenic Mutation Probability in Cancer Patients. Methods in molecular biology (Clifton, N.J.). 2020.", "tier": "A", "kind": "primary", "pmid": "32162254", "doi": "10.1007/978-1-0716-0389-5_8", "url": "https://pubmed.ncbi.nlm.nih.gov/32162254/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32162254", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC3", "CSC6" ] }, { "n": 15, "citation": "McGranahan N, Rosenthal R, Hiley CT et al. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell. 2017.", "tier": "A", "kind": "primary", "pmid": "29107330", "doi": "10.1016/j.cell.2017.10.001", "url": "https://pubmed.ncbi.nlm.nih.gov/29107330/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29107330", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph29, 1:Results:paragraph30, 1:Results:paragraph65. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC4", "CSC6" ] }, { "n": 16, "citation": "Puttick C, Jones TP, Leung MM et al. MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution. Nature genetics. 2024.", "tier": "A", "kind": "primary", "pmid": "39358601", "doi": "10.1038/s41588-024-01883-8", "url": "https://pubmed.ncbi.nlm.nih.gov/39358601/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39358601", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC4" ] }, { "n": 17, "citation": "Dijkstra KK, Vendramin R, Karagianni D et al. Subclonal immune evasion in non-small cell lung cancer. Cancer cell. 2025.", "tier": "A", "kind": "primary", "pmid": "40614739", "doi": "10.1016/j.ccell.2025.06.012", "url": "https://pubmed.ncbi.nlm.nih.gov/40614739/", "status_flags": [ "ErratumIn: PMID42155448" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40614739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC4" ] }, { "n": 18, "citation": "Pathria P, Gotthardt D, Prchal-Murphy M et al. Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice. Oncoimmunology. 2015.", "tier": "A", "kind": "primary", "pmid": "26137415", "doi": "10.1080/2162402X.2014.998529", "url": "https://pubmed.ncbi.nlm.nih.gov/26137415/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26137415", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC1", "CSC4" ] }, { "n": 19, "citation": "Hong WF, Zhang F, Wang N et al. Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2024.", "tier": "A", "kind": "primary", "pmid": "39002266", "doi": "10.1016/j.drup.2024.101115", "url": "https://pubmed.ncbi.nlm.nih.gov/39002266/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39002266", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC4" ] }, { "n": 20, "citation": "Houlahan KE, Khan A, Greenwald NF et al. Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity. Science (New York, N.Y.). 2024.", "tier": "A", "kind": "primary", "pmid": "38815010", "doi": "10.1126/science.adh8697", "url": "https://pubmed.ncbi.nlm.nih.gov/38815010/", "status_flags": [ "UpdateOf: PMID36993286" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38815010", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC3", "CSC6" ] }, { "n": 21, "citation": "Zhou Y, Mo S, Cui H et al. Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma. National science review. 2024.", "tier": "A", "kind": "primary", "pmid": "38803565", "doi": "10.1093/nsr/nwae150", "url": "https://pubmed.ncbi.nlm.nih.gov/38803565/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38803565", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC3", "CSC6" ] }, { "n": 22, "citation": "Lakatos E, Gunasri V, Zapata L et al. Epigenetically driven and early immune evasion in colorectal cancer evolution. Nature genetics. 2025.", "tier": "A", "kind": "primary", "pmid": "41193656", "doi": "10.1038/s41588-025-02349-1", "url": "https://pubmed.ncbi.nlm.nih.gov/41193656/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41193656", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC5", "CSC6", "CH" ] }, { "n": 23, "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.", "tier": "A", "kind": "primary", "pmid": "41043437", "doi": "10.1016/j.ccell.2025.09.005", "url": "https://pubmed.ncbi.nlm.nih.gov/41043437/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41043437", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC1", "CSC3", "CSC5" ] }, { "n": 24, "citation": "He S, Sun S, Liu K et al. Comprehensive assessment of computational methods for cancer immunoediting. Cell reports methods. 2025.", "tier": "A", "kind": "primary", "pmid": "40132544", "doi": "10.1016/j.crmeth.2025.101006", "url": "https://pubmed.ncbi.nlm.nih.gov/40132544/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40132544", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC3" ] }, { "n": 25, "citation": "Lakatos E, Williams MJ, Schenck RO et al. Evolutionary dynamics of neoantigens in growing tumors. Nature genetics. 2020.", "tier": "A", "kind": "primary", "pmid": "32929288", "doi": "10.1038/s41588-020-0687-1", "url": "https://pubmed.ncbi.nlm.nih.gov/32929288/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32929288", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC3" ] }, { "n": 26, "citation": "Roerden M, Castro AB, Cui Y et al. Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression. Journal for immunotherapy of cancer. 2024.", "tier": "A", "kind": "primary", "pmid": "39521615", "doi": "10.1136/jitc-2024-010249", "url": "https://pubmed.ncbi.nlm.nih.gov/39521615/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39521615", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC1", "CSC4" ] }, { "n": 27, "citation": "AbdulJabbar K, Raza SEA, Rosenthal R et al. Geospatial immune variability illuminates differential evolution of lung adenocarcinoma. Nature medicine. 2020.", "tier": "A", "kind": "primary", "pmid": "32461698", "doi": "10.1038/s41591-020-0900-x", "url": "https://pubmed.ncbi.nlm.nih.gov/32461698/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32461698", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C27", "CSC4", "CSC6" ] }, { "n": 28, "citation": "Van den Eynden J, Jiménez-Sánchez A, Miller ML et al. Lack of detectable neoantigen depletion signals in the untreated cancer genome. Nature genetics. 2019.", "tier": "A", "kind": "primary", "pmid": "31768072", "doi": "10.1038/s41588-019-0532-6", "url": "https://pubmed.ncbi.nlm.nih.gov/31768072/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31768072", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph4, 0:Results:paragraph13, 0:Results:paragraph14, 0:Results:paragraph17. No complete-paper or supplement audit claimed.", "carries_claims": [ "C28", "CSC3", "CSC6", "CH" ] }, { "n": 29, "citation": "Castro A, Ozturk K, Pyke RM et al. Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes. BMC medical genomics. 2019.", "tier": "A", "kind": "primary", "pmid": "31345234", "doi": "10.1186/s12920-019-0544-1", "url": "https://pubmed.ncbi.nlm.nih.gov/31345234/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31345234", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C29", "CSC3", "CSC4" ] }, { "n": 30, "citation": "Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. 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