In plain terms

The claim being assessed: Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.

Where the evidence stands: Ζ — Several independent lines agree. Different kinds of evidence, which could not all be wrong for the same reason, point the same way.

What this mechanism does: This makes the process worse or keeps it going, but something else starts it.

Strongest evidence for it: Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means for Immune Surveillance Hypothesis

Claim being assessed: Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.. This review asks whether the proposed factor causes the health outcome—not just whether the two appear together. For the wording assessed here, the evidence is rated Several independent lines agree (HSEF Ζ; Moderate confidence). Different kinds of evidence, which could not all be wrong for the same reason, point the same way. That rating applies to this claim and scope; it does not mean the biological process is irrelevant in every setting.

Implications for health and treatment: This is an assessment of a causal explanation, not proof that a particular supplement, diet, test, or treatment improves health. A treatment claim needs studies that test the intervention in people and measure meaningful benefits and harms. These findings can help frame research and informed clinical questions, but they do not identify what is right for one person.

Limits for individual care: Evidence from cells, animals, associations, or a plausible mechanism may not predict what happens in people. The grade is limited to the exact claim, outcomes, and sources reviewed, and it is not a diagnosis or an individual forecast. Do not start, stop, or change care based on this page; discuss personal decisions with a qualified clinician.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

This assessment rests on 65 sources and 69 individually checked claims. 69 of those claims were verified against the original paper.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

ID	Sub-claim	Type	Level	Pivotal card
SC1	Immune surveillance prevents or restrains emergence of clinical malignancy.	necessity	Ζ	Card ↗
SC2	Immune surveillance causally controls established tumours.	necessity	Η	Card ↗
SC3	Immune-mediated elimination rather than equilibrium or nonimmune dormancy explains latent-cell control.	mechanism	Γ	—

Visual Evidence Cards · Pivotal Subclaims

Pivotal subclaim illustrations

Dark-theme simulated-micrograph renders and concise causal evidence summaries for the pivotal subclaims that govern this review's grade. Click any card to inspect the master 2400×2400 render.

Master 2400×2400 render ↗

Master 2400×2400 render ↗

Figures

Explanatory figures summarizing this review. They carry no evidential weight of their own; where a figure and the review differ, the review governs.

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 65 primary reports; claims: 69; verified: 69; unverified: 0. Verification is bounded attribution. Access: 5 partial-body and 60 complete abstract/status examinations. Literature cutoff: 2026-10-05; source examination UTC date: 2026-10-06. No complete-paper audit or blinded calibration claimed. Adversarial review: Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-06. 1 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

Immune recognition causally restrains cancer emergence and progression in defined contexts; elimination, equilibrium and escape are distinct outcomes.

Deciding experiment: Prospectively trace antigen-defined premalignant clones in a prespecified high-risk human tissue and pair serial viable-cell/immune-contact measures with a narrowly targeted, ethically acceptable interception or rigorous natural immune-pathway contrast.

Belief versus evidence: Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument.

Best-supported rival: Immune equilibrium and context-dependent editing. In a defined occult lesion, serial viable-cell detection plus delayed selective resident-cell depletion distinguishes elimination from equilibrium; matched antigen-negative and intrinsic-quiescence controls distinguish immune editing from nonimmune arrest.

COMPETING MECHANISTIC MODELS

Rank 1: Immune equilibrium and context-dependent editing (Ζ). Immune cells can suppress outgrowth while viable cells survive and escape. Timed dormancy, cytokine blockade and cell-transfer studies support restraint (PMID18026089, PMID33536445, PMID30598548). Some antigenic tumours are eliminated; equilibrium is not the only fate.

Rank 2: Immune recognition and elimination (Ζ). Transformed-cell recognition can remove susceptible cells and shape tumour emergence. Antigen-specific editing/restoration and innate receptor tests, with clinical targeted control, support causal contribution. Antigen-poor tumours, incomplete clearance and null vaccine trials reject uniform sufficiency.

Rank 3: Cell-intrinsic stealth and quiescence (Ε). Latent cells reduce cycling and recognition to survive. DKK1/SOX and STING/NK-related perturbations identify defined escape states (PMID27015306, PMID39106452). Timed immune depletion shows that intrinsic traits do not wholly explain control.

Rank 4: Niche and competition-mediated dormancy (Ε). Mechanical, stromal and cell-competition contexts restrain or promote residual cells. SPARC and stiffness perturbations change outgrowth (PMID36098678, PMID42520796). Niche mechanisms interact with immune recognition and are not generally independent of immunity.

Rank 5: Inflammatory or microbial promotion (Ε). Some immune or microbial states accelerate tumour growth or impair therapy. NK VEGFA and microbial MAdCAM/regT17 manipulations show bounded promotion (PMID26873347, PMID37289890). Protective NK/T-cell contexts and targeted clinical responses preclude uniform promotion.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Innate and adaptive immune surveillance causally suppresses the emergence and progression of cancers by recognizing and controlling transformed cells.

SC1 prevention/emergence is the gate for the surveillance claim. Established-tumour immunotherapy efficacy is reported separately as SC2. Viral control, occult outgrowth and actual transformation prevention are not interchangeable.

Selection: public-interest rank 18 from the editorial ranking compiled 2026-09-23; categorical prior verdicts were visible. Private fresh review; earlier documents are preserved.

Evidence and causal interpretation

Cancer suppression is causally established in defined systems rather than inferred only from immune infiltrates. Native antigen loss/restoration and timed immune perturbations distinguish recognition from generalized sick-host effects; spontaneous and chemically induced models differ in antigenicity (PMID22318517, PMID22318521, PMID18394936, PMID23475219).

Human incidence evidence is real but restricted. Broad transplant excess mixes infection, underlying disease, treatment and detection. Australian graft-failure reversibility is strongest for NHL/lip/melanoma and is not significant for adjusted HPV groups; follicular lymphoma and several common cancers lack the same excess pattern. Randomized ART and HPV interventions establish infection-linked prevention, not selective elimination of every nonviral nascent clone (PMID20150194, PMID20178100, PMID28606585, PMID17721103, PMID35149535).

Targeted clinical perturbations provide substantial causal credit. Checkpoint and antigen-directed cellular therapies alter hard endpoints across tumour types; adjuvant PD1 blockade restrains residual outgrowth. CAR-T unadjusted survival is crossover-limited, and failed vaccines/T-VEC additions show that antigen recognition or immune stimulation is not sufficient in every regimen (PMID39282897, PMID38452313, PMID40623279, PMID28844499, PMID35998300, PMID24019551).

Equilibrium is a positive alternative to sterilizing surveillance. Breast CD8 transfer leaves viable noncycling cells, cytokine blockade permits awakening, and tissue-resident T cells or macrophages restrain specific compartments. The breast human subset was selected for relapse and its association was not independent in Cox analysis; that translational bridge remains observational (PMID18026089, PMID33536445, PMID30598548, PMID39378878).

Recent conditional platelet/T-cell epistasis and metabolite/trafficking experiments resolve protective and promotional contexts. Aspirin-like COX1 effects require the relevant TXA2-ARHGEF1 pathway in tested models and can be reversed by analogue exposure; these findings do not supply a human treatment recommendation or prove first-transformation prevention (PMID40044852, PMID37289890, PMID26873347).

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: scope-matched. Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument. Sensitivities: weakest-link Γ; primary-subclaim Ζ; scope-matched Ζ.

Decisive-perturbation inventory and causal tally

[1] Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity. Constitutive immune deficiency has developmental and host-wide effects; tumour emergence does not directly observe destruction of each initial transformed clone or quantify human prevention.

[2] IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity. Global signalling and p53 sensitization affect intrinsic fitness as well as immune recognition; effects cannot all be assigned to one mature effector cell type.

[3] Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged. Constitutive effector deletion has homeostatic/developmental effects; lymphoma-specific protection does not imply universal prevention or show which nascent clones were eliminated.

[4] Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models. Several outcomes come from imposed tumour-cell models; constitutive genotype and strain dependence constrain broad human emergence and single-mechanism necessity.

[5] Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection. Beta2m alters several recognition pathways and cell development; transplanted-tumour rejection tests differ from native initial emergence and exact recognition pathways remained unresolved.

[6] NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures. Constitutive receptor deletion and oncogene-transgenic backgrounds still constrain generalization; the linked correction changes an author middle initial, not the reported experiment.

[7] Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice. Strain-specific effects and constitutive deficiency limit specificity; shared effector genotypes and laboratory models are not fully independent causal lines.

[8] Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin. Oncogene sensitization and NK-depletion selectivity require caution; delayed clinical emergence is distinct from prevention of hyperplasia or longer survival.

[9] Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice. Increased mammary remnants reflect an embryonic developmental effect; altered tissue at risk must be separated from adult immune surveillance, while salivary growth and histology are distinct outcomes.

[10] T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand. Defined B-cell driver and murine host context establish a specific dependency, without implying every cancer or a universal immune effector module.

[11] Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer. Constitutive receptor changes require developmental controls; linked erratum details lack an identifier in PubMed and are not resolved here, limiting fine-detail claims.

[12] DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement. Highly immunogenic transplanted cells test rejection rather than initial natural transformation; Itgax targeting and chimeric compartments have defined specificity limits.

[13] Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2. Carcinogen-derived and transplanted unedited clones are proxies for nascent disease; selection against antigens does not prove eradication of all early transformed cells.

[14] Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss. Original Results distinguish introduced LucOS antigens from native oncogenic induction: antigen tolerance gave a nonsignificant susceptibility trend, and most fresh antigenic transplants showed delay rather than rejection. Antigen re-expression restored growth restraint; the antigen-free latency contrast was not significant.

[15] Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss. Artificial antigenicity and different native versus transplant contexts limit generalization; untreated native tumours escaped despite continuing antigen expression.

[16] A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells. Overexpressed model antigen and tolerance engineering do not establish common human rates; demonstrates possible recognition failure rather than absence of all surveillance.

[17] Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them. Model transplantation antigens and defined driver restrict scope; direct recognition can coexist with tolerance, opposing automatic editing or elimination without excluding surveillance in other settings.

[18] Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles. Broad adaptive deficiency and mutagenesis architecture complicate generalization; editing without efficient clearance distinguishes restraint from universal removal.

[19] Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence. IL15 has multiple developmental functions; tissue residency and growth effects require cell-resolved reconstitution before attributing every component to one mature cell population.

[20] Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations. Human survival correlations do not establish prevention; different RCC histologies and cytokine effects limit universal extrapolation, and a linked correction remains flagged. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.

[21] Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth. Transfer and engineered signalling test therapeutic capability; human cell surveys and self-antigen reactivity do not directly observe initial clone elimination in patients.

[22] Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas. Engineered antigens and murine sarcomas narrow scope; delayed/fewer emergent tumours and antigen-negative reservoirs do not establish universal sterilizing prevention.

[23] CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells. Defined native HNSCC model and checkpoint intervention support immune control; human marker expression and sorted tumour capacity do not directly demonstrate prevention.

[24] Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing. Constitutive regulator loss affects antigen presentation across compartments; chemical carcinogenesis and transplant follow-up do not establish every human histology's dependence.

[25] HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems. Human circulating-cell expression is observational; platelet RGS18 and HLA-E manipulations test escape from control, not ordinary human cancer emergence.

[26] Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity. Mechanical changes also affect intrinsic metastatic fitness, and immunodeficient comparisons do not alone isolate the immune mediator; human infiltration associations remain observational.

[27] NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2. Engineered survival rescue is not ordinary NK physiology; results oppose uniformly protective immune activation while identifying a specific pro-tumour pathway.

[28] Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function. Constitutive deficiency can affect development and other compartments; colonization and microbiome checks narrow but do not eliminate those alternatives.

[29] Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control. Antibiotics are pleiotropic; NKT functional dependence supports liver-specific control rather than universal benefit of microbiome depletion.

[30] Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy. Human serum MAdCAM prognosis does not isolate causality; results address therapy and microbial immune context rather than native transformation prevention.

[32] Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems. Scarce encounters explain incomplete surveillance. Treatment-mediated elimination does not establish routine sterilizing surveillance; original body was inaccessible in this examination.

[33] SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance. Selected human-derived cell lines and imposed dissemination establish escape capability, not frequency of native human dormancy.

[34] Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells. Transplantable antigenic melanoma remains a defined scope; about 40 percent macroscopic control and about 20 percent awakening after depletion show neither complete elimination nor exclusive immune dependence. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.

[35] Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape. Abstract-level examination supports the equilibrium distinction; exact depletion timing and doses were not independently verified in original Methods.

[36] TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth. Original Methods select 54 patients already known to relapse; the infiltrate association was not independent in multivariable Cox analysis. Native untagged priming and timed cell/cytokine perturbations support mouse dormancy, and transfer left viable noncycling cells; clinical elimination remains unproved.

[37] Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells. Transplanted cell lines and model-specific dependencies narrow generalization; human estrogen-positive lifetime recurrence is background rather than direct prospective mediator evidence.

[38] Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening. This restrains established disseminated cells rather than eliminating them or preventing initial transformation; tumour promotion by other macrophage states remains compatible.

[39] T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects. Original Methods/Results include injected B16/LL2 dissemination and native MMTV-PyMT follow-up, T-cell Arhgef1 conditional deletion, platelet COX1 loss and TXA2-analogue reversal. Effects are epistatic and model-specific; human aspirin immune mediation and initial transformation prevention are not tested.

[40] SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse. Human renal-cancer subclone associations do not prove intervention efficacy; intrinsic competition can coexist with immune restraint.

[41] USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies. Registry ascertainment, genotype syndromes and infection differ from controls; absence of significant common-solid excess constrains uniform protection rather than disproving all surveillance.

[42] Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation. Organ-specific underlying disease, surveillance and drugs are competing causes; early liver cancers can predate transplant and are not new transformation events.

[43] Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated. Original Methods exclude the first three months of each period, leaving 7809 analysable patients from 8173 enrolled. HPV-associated site reductions were not significant in adjusted comparisons. Graft failure changes dialysis/exposures; melanoma is not a proven virus-caused cancer, and persistent risks do not exclude earlier immune effects.

[44] Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer. Small site-specific counts, infection and registration selection limit generalized inference; antibody and T-cell defects are not interchangeable surveillance instruments.

[47] Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference. The intervention jointly changes virus suppression and immune function; it supports clinical infection-linked prevention rather than uniquely isolating transformed-cell recognition.

[48] Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers. Dialysis-associated biology and surveillance can explain part of the overlap; independent geography does not remove the shared immune-deficiency exposure confounding.

[50] US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess. Site and regimen specificity oppose uniform risk; conditional absence of excess does not prove immune irrelevance, and source patients overlap other transplant reports.

[51] Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess. Follicular counts were small with wide intervals; subtype contrast supports restricted immunity/infection effects rather than a universal lymphoma mechanism.

[54] English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments. The mediator is infection prevention, not direct recognition of transformed cells; age-period effects and screening remain natural-experiment limitations.

[55] Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls. Controls combine randomized placebo and population cohorts; few events yield a very wide efficacy interval. Infection blockade is not transformed-cell surveillance alone.

[56] Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine. Engineered checkpoint release demonstrates clinical control capacity, with substantial immune toxicity; it does not establish routine prevention in untreated hosts. An unidentified erratum needs qualification.

[57] Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time. Immune response and survival are not interchangeable with progression or mediation; the treatment is engineered and not ordinary surveillance.

[58] Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC. Open-label treatment and previously treated disease narrow scope; receptor blockade provides targeted causal capacity without proving natural emergence prevention.

[59] Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival. Long-term tail and medians differ; established treated tumours are not nascent transformed-cell emergence, and clinical benefit does not alone prove every mediator step.

[60] CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab. Original Methods identify 945 randomized patients and powered nivolumab-containing versus ipilimumab comparisons; combination versus nivolumab and melanoma-specific survival were descriptive/post hoc. Three-year landmark survivors are selected after treatment, and survival is not verified sterilizing clearance.

[61] Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection. This causally restrains residual-disease outgrowth, not the first transformed cell; survival benefit and elimination of every dormant cell are not established by these endpoints.

[62] Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL. Unadjusted overall-survival confidence intervals included no effect, with extensive crossover; adjusted estimates are model-dependent. Engineered antigen recognition supports control capacity.

[63] ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population. A failed antigen/vaccine regimen constrains general treatment sufficiency, not the existence of immune tumour control in other contexts.

[64] Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases. Incremental combination failure is not failure of the active checkpoint backbone or proof against immune surveillance.

[65] GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping. Later overall-survival intervals included no effect. Antibody induction is not proof of beneficial transformed-cell killing or a sufficient clinical endpoint.

Tally: 59 discriminating contrasts. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. GW vaccination is an infection-control lead, not a cancer endpoint. A native induced tumour can still carry introduced antigen. Specific antigen tolerance and adjusted HPV comparisons include nonsignificant results; neither is overstated.

Cap audit, precedence and Β/Γ/Δ boundary

Rubric05 admits targeted clinical therapy, inborn-immunity natural experiments and incidence/depletion endpoints. Broad suppression alone does not cross Δ; timed native immune tests and antigen loss/restoration do. Human adjuvant recurrence prevention directly tests emergence from residual cells, while HPV vaccination tests infection prevention and is not substituted for transformed-cell sensing. These classes fail differently and are scored as a convergent set; neither an unethical prevention-RCT requirement nor a weakest-member cap is imposed. SC3 is an unmet positive elimination-dominance burden, not a literal Gamma hard rule.

Gamma hard-rule audit: Broad immunosuppression alone remains pleiotropic and is not Strong evidence. Developmental immune knockouts require conditional/timed or antigen-specific convergence. Infiltrate/cytotoxicity associations are not tumour-specific elimination. The assembled set contains native timed, antigen-restoration and clinical targeted perturbations; an isolated-class Gamma cap is not reapplied to it.

SC1 field-valid definition: “ - Cell-type-specific conditional knockout or depletion - Pathway-specific blockade (not broad immunosuppression) changing disease course - Human targeted therapy with mechanistic alignment showing disease-modifying effect” Positive full-scope result: yes. Timed endogenous tumour tests, antigen-specific loss/restoration, cell-resolved immune perturbations and human immune-status/adjuvant contrasts converge on restraint of clinical emergence. The human contribution varies by histology and viral status; this is a causal contribution, not universal necessity or prevention of every first mutation. Human selective nonviral nascent-cell elimination remains unmeasured, preventing a robust upstream all-system Η claim.

SC2 field-valid definition: “ - Cell-type-specific conditional knockout or depletion - Pathway-specific blockade (not broad immunosuppression) changing disease course - Human targeted therapy with mechanistic alignment showing disease-modifying effect” Positive full-scope result: yes. Targeted checkpoint, antigen-directed cellular therapy and vaccine interventions alter hard clinical outcomes across melanoma, lung, prostate and lymphoma, alongside independent conditional depletion/rescue systems. This establishes robust causal control capacity across interventions, with defined antigen, stage and treatment boundaries. Null vaccine and combination trials prevent predictive near-universal Θ.

SC3 field-valid definition: “ - Cell-type-specific conditional knockout or depletion - Pathway-specific blockade (not broad immunosuppression) changing disease course - Human targeted therapy with mechanistic alignment showing disease-modifying effect” Positive full-scope result: no. Elimination is possible, but viable occult cells and timed dormancy breakdown directly demonstrate equilibrium; scarcity, intrinsic quiescence and niche signals also limit clearance. Thus elimination as the predominant explanation is plausible in some settings but is not established across the registered latent-cell scope.

Upward threshold ladder

SC1 Δ: “Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.” Satisfied: yes.

SC1 Ε: “Requires context-specific causality with explicit scope restriction.” Satisfied: yes.

SC1 Ζ: “Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.” Satisfied: yes.

SC1 Η: “Requires robust upstream causal evidence across systems and interventions.” Satisfied: no. Independent prospective human antigen/immune mediator tracing before clinical emergence, with a selective perturbation or rigorous natural instrument, shows early nonviral-cell restraint beyond infection prevention and across prespecified tissue settings.

SC2 Δ: “Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.” Satisfied: yes.

SC2 Ε: “Requires context-specific causality with explicit scope restriction.” Satisfied: yes.

SC2 Ζ: “Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.” Satisfied: yes.

SC2 Η: “Requires robust upstream causal evidence across systems and interventions.” Satisfied: yes.

SC2 Θ: “Requires predictive consistency and minimal contradiction in the claimed disease scope.” Satisfied: no. Prespecified antigen/context models predict response and nonresponse across independently held-out tumour settings with few unexplained failures; complete necessity and sufficiency require dedicated elimination/rescue tests.

SC3 Δ: “Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.” Satisfied: no. Serial viable-cell quantification distinguishes actual elimination from arrest, then timed selective depletion tests for residual outgrowth with nonimmune dormancy controls.

Upper ladder: Inborn-immunity contrasts, immune-status reversibility, ART randomization, adjuvant PD1 control and targeted checkpoint/CAR-T trials make upper levels reachable. SC1 crosses Ζ as causal restraint, but direct selective early human nonviral recognition remains unresolved for Η; SC2 crosses Η, while reproducible failures and incomplete antigen predictability stop Θ. No universal necessity/sufficiency claim crosses Ω.

Independence: 65 reports do not mean 65 independent causal lines. Registry overlap, one Japanese cohort, shared murine lineage/antigen platforms and repeated trial follow-up are identified. Orthogonal timing, antigen restoration, innate pathways and human clinical perturbations support convergence without pooling them as an incidence fraction.

Native antigen and timing [14, 13, 35]: Separates recognition/editing/equilibrium from transplantation capacity, though induced mouse antigens remain scope-limited.

Innate receptor and cell pathways [6, 19, 39]: Tests mechanisms with failure modes distinct from adaptive antigen assays.

Human immune-status reversibility [43, 41, 47]: Tests clinical emergence across exposure classes; infection and underlying disease remain confounders.

Targeted human residual and established control [61, 60, 58, 62]: Randomization and distinct clinical receptor/antigen targets exclude a purely observational or downstream-marker explanation.

Falsification and pitfalls

Antigen-poor native tumours develop despite intact immunity. PMID16136144 and PMID23475219 limit automatic surveillance and uniform recognition. Additional downgrade: False.

Dormant viable cells survive under protective immunity. PMID18026089, PMID30598548 and PMID33536445 reject elimination-exclusive control. Additional downgrade: False.

Immune manipulation can fail or promote cancer. PMID26873347, PMID28844499, PMID35998300 and PMID24019551 constrain uniform therapeutic benefit. Additional downgrade: False.

Macroscopic tumour-free status treated as elimination. Equilibrium and residual dissemination models.

Virus prevention equated with transformed-cell sensing. HPV vaccine, HIV and transplant incidence evidence.

Established immunotherapy benefit treated as natural prevention frequency. Checkpoint and CAR-T trials.

Immune activation always called protective. NK VEGFA and regulatory trafficking.

Provider or publication counts treated as independent evidence. Consensus screen counts, shared cohorts and repeated endpoints.

Adversarial steelman: above, then below

Η for SC1 is defensible if the combination of native selective recognition tests, clinical residual-disease prevention and natural human exposure reversibility is judged to resolve upstream emergence across systems. It remains blocked here by missing direct early nonviral human recognition attribution; progression capacity cannot simply supply that step.

Ε would restrict the claim to one context despite independently targeted native, innate/adaptive and human hard-endpoint perturbations that exclude a downstream-marker-only account. The registered statement is causal suppression, not universal elimination.

Ζ balances convergent causal restraint with incomplete direct human emergence mediation. SC2 earns Η; SC3 Γ is explicitly separate and does not redefine suppresses as sterilizes.

Final score, causal direction and M/S/D

Ζ for the preregistered SC1 scope-matched emergence-restraint gate, with Η established-tumour control and Γ elimination-dominance reported separately. The nominal claim says suppresses emergence/progression, not that all cancers require failed immunity or that suppression must sterilize cells. Weakest-link Γ is an explicit sensitivity to the additional elimination-exclusive subclaim, not a reason to demote the nominal restraint claim. The assembled set crosses Δ/Ε/Ζ through temporally and antigen-resolved native tests, orthogonal innate/adaptive mechanisms, human immune-status contrasts and randomized residual-outgrowth prevention; no single broad-deficiency leg is used as the sole instrument.

Immune recognition is an extrinsic protective causal restraint: it can prevent outgrowth, maintain equilibrium or eliminate susceptible cells, while failed recognition and promotional immune states permit progression. It is not a universal initiator of cancer; the role vocabulary describes stabilization of the nonmalignant/dormant state.

Momentum: Mechanistic only. The named programmes in this corpus — conditional platelet COX1/TXA2-ARHGEF1 epistasis, microbial MAdCAM and regT17 trafficking manipulation, and SPARC/stiffness dormancy perturbation — test mechanistic and functional boundaries. No presently recruiting study addressing the SC1 Eta boundary check, prospective human tracing or interception of nonviral nascent clones before clinical emergence, is identified.

Stability: Stable. No named pending result is asserted to be likely to move the registered score imminently.

Divergence: Contested; no single implied-level arithmetic. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

Prospectively trace antigen-defined premalignant clones in a prespecified high-risk human tissue and pair serial viable-cell/immune-contact measures with a narrowly targeted, ethically acceptable interception or rigorous natural immune-pathway contrast.

Readout: Clone survival, malignant conversion, immune engagement and subsequent clinical emergence. Controls: Baseline antigen-negative clones, virus status, intrinsic growth traits and surveillance intensity; distinguish viable dormancy from absent detection. Supporting: Selective recognition engagement reduces conversion/outgrowth with a mediator-consistent contrast and independent replication. Falsifying: Engagement changes immune markers without clone fate or clinical emergence, or nonimmune traits fully explain the contrast.

RESEARCH TIMELINE

KNOWLEDGE GAPS

Direct measurement of human nonviral nascent-cell recognition before diagnosis.

Validated viable-cell markers separating elimination from equilibrium.

Predictive receptor/antigen rules for protective versus promotional immune states.

Independent human immune instruments separated from infection, drug carcinogenicity and detection.

Low-toxicity interception trials with hard emergence endpoints and predefined safety/net benefit.

Mechanism-specific recurrence outcomes that distinguish persistent dormancy from cure.

METHODS AND CONSENSUS CONTRIBUTION

Consensus was used through the signed-in browser for discovery, counterevidence, research-gap and timeline suggestions, and attempted checks of specific indexed full-text passages. Returned Methods/Results passages were reconciled with original-paper passages where available; failed retrievals, source substitutions and unverified aspects are recorded in the case reconciliation. Successful passage checks are distinguished from provider summaries. Provider screening counts, citation counts and meters were not used as primary counts or HSEF scores. This source log records access depth; it does not claim complete-paper or supplement review. The monthly API allowance was conserved: zero Consensus API calls in this batch.

REVIEWER NOTES

65 primary reports actually presented and appraised; five have selected original body examinations. GW vaccination remains an explicitly indirect infection-control lead, not a cancer endpoint. Two correction identities and several unidentified linked errata are recorded but substantive text remains unresolved; no cleared-status claim is made. Two Consensus browser queries informed gaps/timeline and indexed checks, reconciled against original sections; API zero. Exact v5.3 structural validation is separate from scientific peer review and new blind calibration.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1. Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-06.

Scope of checks. All 65 reference PMIDs re-resolved against PubMed (65/65 correct for first author, title, journal and DOI; no retraction or expression of concern; six linked errata already recorded in the ledger's status_flags). Eleven load-bearing claims spot-checked against primary abstracts: DuPage 2012 and Matsushita 2012 antigen-resolved editing, Koebel 2007 equilibrium, Park 2018 resident-memory melanoma control (about 40 per cent macroscopically lesion-free), van Leeuwen 2010 reversibility after transplant failure (non-Hodgkin lymphoma IRR 0.20, lip 0.04, melanoma 0.16), Vajdic 2010 absence of excess follicular lymphoma, Mayor 2017 primary immunodeficiency excess risk, Wolchok 2024 CheckMate 067 ten-year follow-up (945 randomized), Luke 2024 KEYNOTE-716 adjuvant pembrolizumab, Kamdar 2025 TRANSFORM, and the null vaccine trials (ACT IV, EORTC 18961, T-VEC plus pembrolizumab). Scoring logic re-derived independently before the existing letter was read, with particular attention to the Ζ independence basis.

Findings.

Rejected findings (checked, no change).

1. Ζ is too high because part of the convergent set is epidemiological. Rejected: hsef-framework.md states that caps "bind the inference from a single evidence class, not from a set that was assembled to cover each other's weaknesses", and the independence basis names four lines with distinct failure modes (native antigen/timing, innate receptor pathways, human immune-status reversibility, randomized targeted intervention).
2. Weakest-link should govern because SC3 is Γ. Rejected: the pre-registered rule is scope-matched, SC1 is the subclaim whose scope matches the registered emergence-and-progression claim, and the weakest-link sensitivity is already reported.
3. SC2 at Η. Checked against the Η descriptor and the rubric's threshold text; randomized checkpoint, cellular-therapy and adjuvant results with hard endpoints support it, and the null vaccine and combination trials are correctly used to block Θ.
4. Citation-year differences of ±1 between printed issue year and PubMed e-pub year (references 34, 41, 49, 60, 64). Publication-convention difference, not an error.

Residual limitations. Verification depth is bounded by access: 5 partial-body examinations and 60 abstract/status examinations. The human arm of the Ζ case remains observational in the sense the review states, and no image or raw-data audit was performed.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-06.

REFERENCES

1. Shankaran V, Ikeda H, Bruce AT et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001. PMID 11323675. DOI: 10.1038/35074122. Access: abstract_metadata. Study: PMID11323675.

2. Kaplan DH, Shankaran V, Dighe AS et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proceedings of the National Academy of Sciences of the United States of America. 1998. PMID 9636188. DOI: 10.1073/pnas.95.13.7556. Access: abstract_metadata. Study: PMID9636188.

3. Smyth MJ, Thia KY, Street SE et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. The Journal of experimental medicine. 2000. PMID 10974040. DOI: 10.1084/jem.192.5.755. Access: abstract_metadata. Study: PMID10974040.

4. Street SE, Cretney E, Smyth MJ et al. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood. 2001. PMID 11133760. DOI: 10.1182/blood.v97.1.192. Access: abstract_metadata. Study: PMID11133760.

5. 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. PMID 15007091. DOI: 10.1084/jem.20031981. Access: abstract_metadata. Study: PMID15007091.

6. Guerra N, Tan YX, Joncker NT et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008. PMID 18394936. DOI: 10.1016/j.immuni.2008.02.016. Access: abstract_metadata. Study: PMID18394936.

7. Street SE, Trapani JA, MacGregor D et al. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. The Journal of experimental medicine. 2002. PMID 12093877. DOI: 10.1084/jem.20020063. Access: abstract_metadata. Study: PMID12093877.

8. 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. PMID 17545627. DOI: 10.1158/0008-5472.CAN-06-4084. Access: abstract_metadata. Study: PMID17545627.

9. Macagno M, Bandini S, Stramucci L et al. Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice. Journal of immunology (Baltimore, Md. : 1950). 2014. PMID 24790144. DOI: 10.4049/jimmunol.1301248. Access: abstract_metadata. Study: PMID24790144.

10. Afshar-Sterle S, Zotos D, Bernard NJ et al. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nature medicine. 2014. PMID 24487434. DOI: 10.1038/nm.3442. Access: abstract_metadata. Study: PMID24487434.

11. Dunn GP, Bruce AT, Sheehan KC et al. A critical function for type I interferons in cancer immunoediting. Nature immunology. 2005. PMID 15951814. DOI: 10.1038/ni1213. Access: abstract_metadata. Study: PMID15951814.

12. 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. PMID 21930769. DOI: 10.1084/jem.20101158. Access: abstract_metadata. Study: PMID21930769.

13. Matsushita H, Vesely MD, Koboldt DC et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012. PMID 22318521. DOI: 10.1038/nature10755. Access: abstract_metadata. Study: PMID22318521.

14. DuPage M, Mazumdar C, Schmidt LM et al. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012. PMID 22318517. DOI: 10.1038/nature10803. Access: full_text_partial. Study: PMID22318517.

15. DuPage M, Cheung AF, Mazumdar C et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer cell. 2011. PMID 21251614. DOI: 10.1016/j.ccr.2010.11.011. Access: abstract_metadata. Study: PMID21251614.

16. Cheung AF, Dupage MJ, Dong HK et al. Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer. Cancer research. 2008. PMID 19010921. DOI: 10.1158/0008-5472.CAN-08-2634. Access: abstract_metadata. Study: PMID19010921.

17. Willimsky G, Blankenstein T et al. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 2005. PMID 16136144. DOI: 10.1038/nature03954. Access: abstract_metadata. Study: PMID16136144.

18. Rogers LM, Olivier AK, Meyerholz DK et al. Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer. Journal of immunology (Baltimore, Md. : 1950). 2013. PMID 23475219. DOI: 10.4049/jimmunol.1203227. Access: abstract_metadata. Study: PMID23475219.

19. Dadi S, Chhangawala S, Whitlock BM et al. Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells. Cell. 2016. PMID 26806130. DOI: 10.1016/j.cell.2016.01.002. Access: abstract_metadata. Study: PMID26806130.

20. Kansler ER, Dadi S, Krishna C et al. Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies. Nature immunology. 2022. PMID 35618834. DOI: 10.1038/s41590-022-01213-2. Access: abstract_metadata. Study: PMID35618834.

21. Chou C, Zhang X, Krishna C et al. Programme of self-reactive innate-like T cell-mediated cancer immunity. Nature. 2022. PMID 35444279. DOI: 10.1038/s41586-022-04632-1. Access: abstract_metadata. Study: PMID35444279.

22. 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. PMID 41043437. DOI: 10.1016/j.ccell.2025.09.005. Access: abstract_metadata. Study: PMID41043437.

23. Wang C, Li Y, Jia L et al. CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance. Cell stem cell. 2021. PMID 33945793. DOI: 10.1016/j.stem.2021.04.011. Access: abstract_metadata. Study: PMID33945793.

24. Shukla A, Cayarga AA, Lucier JF et al. Essential Role of NLRC5 in Cancer Immune Surveillance and Cancer Immunoediting. Scandinavian journal of immunology. 2025. PMID 40820374. DOI: 10.1111/sji.70047. Access: abstract_metadata. Study: PMID40820374.

25. Liu X, Song J, Zhang H et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer cell. 2023. PMID 36706761. DOI: 10.1016/j.ccell.2023.01.001. Access: abstract_metadata. Study: PMID36706761.

26. Elbanna YA, Tello-Lafoz M, Holland A et al. Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells. Immunity. 2026. PMID 42520796. DOI: 10.1016/j.immuni.2026.06.025. Access: abstract_metadata. Study: PMID42520796.

27. Gotthardt D, Putz EM, Grundschober E et al. STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion. Cancer discovery. 2016. PMID 26873347. DOI: 10.1158/2159-8290.CD-15-0732. Access: abstract_metadata. Study: PMID26873347.

28. Dupaul-Chicoine J, Arabzadeh A, Dagenais M et al. The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity. Immunity. 2015. PMID 26384545. DOI: 10.1016/j.immuni.2015.08.013. Access: abstract_metadata. Study: PMID26384545.

29. Ma C, Han M, Heinrich B et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science (New York, N.Y.). 2018. PMID 29798856. DOI: 10.1126/science.aan5931. Access: abstract_metadata. Study: PMID29798856.

30. Fidelle M, Rauber C, Alves Costa Silva C et al. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science (New York, N.Y.). 2023. PMID 37289890. DOI: 10.1126/science.abo2296. Access: abstract_metadata. Study: PMID37289890.

31. Huang Y, Ma C, Zhang Q et al. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget. 2015. PMID 25968569. DOI: 10.18632/oncotarget.3958. Access: abstract_metadata. Study: PMID25968569.

32. Goddard ET, Linde MH, Srivastava S et al. Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies. Cancer cell. 2024. PMID 38194912. DOI: 10.1016/j.ccell.2023.12.011. Access: abstract_metadata. Study: PMID38194912.

33. Malladi S, Macalinao DG, Jin X et al. Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell. 2016. PMID 27015306. DOI: 10.1016/j.cell.2016.02.025. Access: abstract_metadata. Study: PMID27015306.

34. Park SL, Buzzai A, Rautela J et al. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature. 2019. PMID 30598548. DOI: 10.1038/s41586-018-0812-9. Access: abstract_metadata. Study: PMID30598548.

35. Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007. PMID 18026089. DOI: 10.1038/nature06309. Access: abstract_metadata. Study: PMID18026089.

36. Tallón de Lara P, Castañón H, Vermeer M et al. CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer. Nature communications. 2021. PMID 33536445. DOI: 10.1038/s41467-021-21045-2. Access: full_text_partial. Study: PMID33536445.

37. Bushnell GG, Sharma D, Wilmot HC et al. Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy. Cancer research. 2024. PMID 39106452. DOI: 10.1158/0008-5472.CAN-24-0030. Access: abstract_metadata. Study: PMID39106452.

38. Dalla E, Papanicolaou M, Park MD et al. Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis. Cell. 2024. PMID 39378878. DOI: 10.1016/j.cell.2024.09.016. Access: abstract_metadata. Study: PMID39378878.

39. Yang J, Yamashita-Kanemaru Y, Morris BI et al. Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity. Nature. 2025. PMID 40044852. DOI: 10.1038/s41586-025-08626-7. Access: full_text_partial. Study: PMID40044852.

40. Kim K, Huang H, Parida PK et al. Cell Competition Shapes Metastatic Latency and Relapse. Cancer discovery. 2023. PMID 36098678. DOI: 10.1158/2159-8290.CD-22-0236. Access: abstract_metadata. Study: PMID36098678.

41. Mayor PC, Eng KH, Singel KL et al. Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. The Journal of allergy and clinical immunology. 2018. PMID 28606585. DOI: 10.1016/j.jaci.2017.05.024. Access: abstract_metadata. Study: PMID28606585.

42. Engels EA, Pfeiffer RM, Fraumeni JF et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011. PMID 22045767. DOI: 10.1001/jama.2011.1592. Access: abstract_metadata. Study: US-transplant-cancer-match.

43. van Leeuwen MT, Webster AC, McCredie MR et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ (Clinical research ed.). 2010. PMID 20150194. DOI: 10.1136/bmj.c570. Access: full_text_partial. Study: Australian-ANZDATA-transplant.

44. Vajdic CM, Mao L, van Leeuwen MT et al. Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood. 2010. PMID 20466855. DOI: 10.1182/blood-2010-03-272351. Access: abstract_metadata. Study: PMID20466855.

45. Imai K, Matsuyama S, Miyake S et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet (London, England). 2000. PMID 11117911. DOI: 10.1016/S0140-6736(00)03231-1. Access: abstract_metadata. Study: Japanese-cytotoxicity-cohort.

46. Hayashi T, Imai K, Morishita Y et al. Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance. Cancer research. 2006. PMID 16397273. DOI: 10.1158/0008-5472.CAN-05-2776. Access: abstract_metadata. Study: Japanese-cytotoxicity-cohort.

47. Silverberg MJ, Neuhaus J, Bower M et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS (London, England). 2007. PMID 17721103. DOI: 10.1097/QAD.0b013e3282ed6338. Access: abstract_metadata. Study: PMID17721103.

48. Hortlund M, Arroyo Mühr LS, Storm H et al. Cancer risks after solid organ transplantation and after long-term dialysis. International journal of cancer. 2017. PMID 27870055. DOI: 10.1002/ijc.30531. Access: abstract_metadata. Study: PMID27870055.

49. Tanaka T, Lynch CF, Yu KJ et al. Pancreatic cancer among solid organ transplant recipients in the United States. Journal of cancer research and clinical oncology. 2023. PMID 35932302. DOI: 10.1007/s00432-022-04227-3. Access: abstract_metadata. Study: US-transplant-cancer-match.

50. Safaeian M, Robbins HA, Berndt SI et al. Risk of Colorectal Cancer After Solid Organ Transplantation in the United States. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016. PMID 26731613. DOI: 10.1111/ajt.13549. Access: abstract_metadata. Study: US-transplant-cancer-match.

51. Vajdic CM, van Leeuwen MT, Turner JJ et al. No excess risk of follicular lymphoma in kidney transplant and HIV-related immunodeficiency. International journal of cancer. 2010. PMID 20178100. DOI: 10.1002/ijc.25272. Access: abstract_metadata. Study: Australian-ANZDATA-plus-HIV.

52. Tribble JT, Pfeiffer RM, Brownell I et al. Merkel Cell Carcinoma and Immunosuppression, UV Radiation, and Merkel Cell Polyomavirus. JAMA dermatology. 2025. PMID 39602110. DOI: 10.1001/jamadermatol.2024.4607. Access: abstract_metadata. Study: PMID39602110.

53. Leval A, Herweijer E, Ploner A et al. Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study. Journal of the National Cancer Institute. 2013. PMID 23486550. DOI: 10.1093/jnci/djt032. Access: abstract_metadata. Study: PMID23486550.

54. Falcaro M, Castañon A, Ndlela B et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet (London, England). 2021. PMID 34741816. DOI: 10.1016/S0140-6736(21)02178-4. Access: abstract_metadata. Study: PMID34741816.

55. Lehtinen M, Lagheden C, Luostarinen T et al. Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial. BMJ open. 2021. PMID 35149535. DOI: 10.1136/bmjopen-2021-050669. Access: abstract_metadata. Study: PMID35149535.

56. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. The New England journal of medicine. 2010. PMID 20525992. DOI: 10.1056/NEJMoa1003466. Access: abstract_metadata. Study: PMID20525992.

57. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England journal of medicine. 2010. PMID 20818862. DOI: 10.1056/NEJMoa1001294. Access: abstract_metadata. Study: PMID20818862.

58. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. The New England journal of medicine. 2015. PMID 26028407. DOI: 10.1056/NEJMoa1504627. Access: abstract_metadata. Study: PMID26028407.

59. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. The New England journal of medicine. 2015. PMID 26412456. DOI: 10.1056/NEJMoa1507643. Access: abstract_metadata. Study: PMID26412456.

60. Wolchok JD, Chiarion-Sileni V, Rutkowski P et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2025. PMID 39282897. DOI: 10.1056/NEJMoa2407417. Access: full_text_partial. Study: PMID39282897.

61. Luke JJ, Ascierto PA, Khattak MA et al. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024. PMID 38452313. DOI: 10.1200/JCO.23.02355. Access: abstract_metadata. Study: PMID38452313.

62. Kamdar M, Solomon SR, Arnason J et al. Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2025. PMID 40623279. DOI: 10.1200/JCO-25-00399. Access: abstract_metadata. Study: PMID40623279.

63. Weller M, Butowski N, Tran DD et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. The Lancet. Oncology. 2017. PMID 28844499. DOI: 10.1016/S1470-2045(17)30517-X. Access: abstract_metadata. Study: PMID28844499.

64. Chesney JA, Ribas A, Long GV et al. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023. PMID 35998300. DOI: 10.1200/JCO.22.00343. Access: abstract_metadata. Study: PMID35998300.

65. Eggermont AM, Suciu S, Rutkowski P et al. Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor > 1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013. PMID 24019551. DOI: 10.1200/JCO.2012.47.9303. Access: abstract_metadata. Study: PMID24019551.

Source-specific evidence cards

[1] IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.

Shows: Lymphocyte and IFNgamma deficiency increased carcinogen-induced sarcomas and spontaneous epithelial cancers, with immune selection reducing surviving tumour immunogenicity.

Does not show: Constitutive immune deficiency has developmental and host-wide effects; tumour emergence does not directly observe destruction of each initial transformed clone or quantify human prevention.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[2] Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.

Shows: IFNgamma receptor or STAT1 deficiency increased chemically induced and p53-background spontaneous tumour occurrence; tumour-cell responsiveness contributed to immunogenicity.

Does not show: Global signalling and p53 sensitization affect intrinsic fitness as well as immune recognition; effects cannot all be assigned to one mature effector cell type.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[3] Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.

Shows: Perforin-deficient mice developed spontaneous lymphomas and showed striking susceptibility to their transplantation, while p53-associated sarcoma timing was unchanged.

Does not show: Constitutive effector deletion has homeostatic/developmental effects; lymphoma-specific protection does not imply universal prevention or show which nascent clones were eliminated.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[4] Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.

Shows: Perforin, IFNgamma and NK perturbations distinguished independent controls of carcinogen-induced sarcomas and transplanted/spontaneous metastasis models.

Does not show: Several outcomes come from imposed tumour-cell models; constitutive genotype and strain dependence constrain broad human emergence and single-mechanism necessity.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[5] Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells.

Shows: Combined perforin/beta2m deficiency accelerated spontaneous B-cell lymphomas, and transfer/depletion experiments implicated NK and gamma-delta effectors in rejection.

Does not show: Beta2m alters several recognition pathways and cell development; transplanted-tumour rejection tests differ from native initial emergence and exact recognition pathways remained unresolved.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[6] NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy.

Shows: NKG2D loss impaired surveillance in two de novo malignancy models without an apparent requirement for NK development; primary tumours expressed ligands and showed editing signatures.

Does not show: Constitutive receptor deletion and oncogene-transgenic backgrounds still constrain generalization; the linked correction changes an author middle initial, not the reported experiment.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC1, SC2.

[7] Suppression of lymphoma and epithelial malignancies effected by interferon gamma.

Shows: Spontaneous lymphoma and late epithelial tumours increased with IFNgamma/perforin loss, while isolated IL12, IL18 or TNF loss did not suffice.

Does not show: Strain-specific effects and constitutive deficiency limit specificity; shared effector genotypes and laboratory models are not fully independent causal lines.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[8] Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma.

Shows: Perforin loss or NK depletion accelerated Her2/neu mammary cancer onset and multiplicity; CD8 depletion did not, and survival was not improved by intact perforin.

Does not show: Oncogene sensitization and NK-depletion selectivity require caution; delayed clinical emergence is distinct from prevention of hyperplasia or longer survival.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[9] Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice.

Shows: Perforin deficiency accelerated salivary and male mammary tumours in neu-transgenic mice.

Does not show: Increased mammary remnants reflect an embryonic developmental effect; altered tissue at risk must be separated from adult immune surveillance, while salivary growth and histology are distinct outcomes.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[10] Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas.

Shows: T-cell impairment allowed rapid B-lineage DLBCL-like outgrowth after Blimp1/Bcl6 alterations; polyclonal CD8 eradication required TCR, CD28 and Fas ligand.

Does not show: Defined B-cell driver and murine host context establish a specific dependency, without implying every cancer or a universal immune effector module.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[11] A critical function for type I interferons in cancer immunoediting.

Shows: Type I interferon perturbation and compartment tests implicated host hematopoietic rather than tumour-cell sensitivity in restraining primary and transplanted cancer.

Does not show: Constitutive receptor changes require developmental controls; linked erratum details lack an identifier in PubMed and are not resolved here, limiting fine-detail claims.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC1, SC2.

[12] Type I interferon is selectively required by dendritic cells for immune rejection of tumors.

Shows: DC-specific Ifnar1 deletion impaired cross-presentation and rejection while NK depletion or myeloid receptor loss did not, resolving a cell-specific immune requirement.

Does not show: Highly immunogenic transplanted cells test rejection rather than initial natural transformation; Itgax targeting and chimeric compartments have defined specificity limits.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[13] Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.

Shows: Exome prediction and antigen validation showed T-cell selection for pre-existing sarcoma clones lacking highly antigenic mutant spectrin-beta2.

Does not show: Carcinogen-derived and transplanted unedited clones are proxies for nascent disease; selection against antigens does not prove eradication of all early transformed cells.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[14] Expression of tumour-specific antigens underlies cancer immunoediting.

Shows: Matched autochthonous sarcomas with controlled antigenicity and specific tolerance demonstrated antigen-recognition-dependent immunoediting and escape through antigen or MHC-I loss.

Does not show: Original Results distinguish introduced LucOS antigens from native oncogenic induction: antigen tolerance gave a nonsignificant susceptibility trend, and most fresh antigenic transplants showed delay rather than rejection. Antigen re-expression restored growth restraint; the antigen-free latency contrast was not significant.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: Original PMC Results and Methods selected lines 103-127,130-160,163-176. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[15] Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.

Shows: Engineered neoantigen expression in native lung tumours elicited endogenous T cells that delayed progression; prophylactic vaccination or transplantation produced stronger clearance or antigen loss.

Does not show: Artificial antigenicity and different native versus transplant contexts limit generalization; untreated native tumours escaped despite continuing antigen expression.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[16] Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer.

Shows: A regulated lung-tumour SIY system identified thymic deletion, peripheral apoptosis, anergy and increased costimulation requirements that limited tumour-reactive T cells.

Does not show: Overexpressed model antigen and tolerance engineering do not establish common human rates; demonstrates possible recognition failure rather than absence of all surveillance.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[17] Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance.

Shows: Rare spontaneous oncogene activation produced immunogenic tumours that induced dysfunctional tumour-reactive T cells; naive mice progressed while vaccination prevented tumours and transplant recipients rejected them.

Does not show: Model transplantation antigens and defined driver restrict scope; direct recognition can coexist with tolerance, opposing automatic editing or elimination without excluding surveillance in other settings.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[18] Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer.

Shows: Sleeping Beauty mutagenesis yielded similar overall latency and multiplicity in wild-type and Rag2-null mice, with tumour-type exceptions and altered genetic profiles.

Does not show: Broad adaptive deficiency and mutagenesis architecture complicate generalization; editing without efficient clearance distinguishes restraint from universal removal.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[19] Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells.

Shows: Early oncogene-driven tumours elicited resident cytotoxic lymphocytes; IL15 but not Nfil3 deficiency accelerated growth, distinguishing nonconventional cells from typical NK dependence.

Does not show: IL15 has multiple developmental functions; tissue residency and growth effects require cell-resolved reconstitution before attributing every component to one mature cell population.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[20] Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies.

Shows: Cancer-cell IL15 supported ILC1 expansion and antitumour function in murine breast cancer, alongside histology-specific human ILC1 associations.

Does not show: Human survival correlations do not establish prevention; different RCC histologies and cytokine effects limit universal extrapolation, and a linked correction remains flagged. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID35705800. Subclaims: SC1, SC2.

[21] Programme of self-reactive innate-like T cell-mediated cancer immunity.

Shows: Self-reactive innate-like T cells depended on tumour IL15, and inducible activation in transferred progenitors suppressed growth.

Does not show: Transfer and engineered signalling test therapeutic capability; human cell surveys and self-antigen reactivity do not directly observe initial clone elimination in patients.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[22] Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas.

Shows: Timed antigen removal, T-cell depletion and IFNgamma blockade distinguished early elimination and bystander restraint of developing fluorescent-neoantigen sarcomas.

Does not show: Engineered antigens and murine sarcomas narrow scope; delayed/fewer emergent tumours and antigen-negative reservoirs do not establish universal sterilizing prevention.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[23] CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance.

Shows: CD276 blockade reduced SCC growth and nodal metastases through CD8-dependent depletion of stem-like tumour cells.

Does not show: Defined native HNSCC model and checkpoint intervention support immune control; human marker expression and sorted tumour capacity do not directly demonstrate prevention.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[24] Essential Role of NLRC5 in Cancer Immune Surveillance and Cancer Immunoediting.

Shows: Nlrc5 deficiency increased endogenous carcinogen-tumour propensity and growth despite preserved CD8 development, while derived lines differed in immune control and editing.

Does not show: Constitutive regulator loss affects antigen presentation across compartments; chemical carcinogenesis and transplant follow-up do not establish every human histology's dependence.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[25] Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance.

Shows: HLA-E knockdown and NKG2A blockade increased NK killing of pancreatic circulating tumour cells and suppressed metastatic progression in experimental systems.

Does not show: Human circulating-cell expression is observational; platelet RGS18 and HLA-E manipulations test escape from control, not ordinary human cancer emergence.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[26] Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells.

Shows: Rigid metastatic niches increased cancer-cell stiffness and immune vulnerability; Spp1 deletion changed colonization and immune sensitivity.

Does not show: Mechanical changes also affect intrinsic metastatic fitness, and immunodeficient comparisons do not alone isolate the immune mediator; human infiltration associations remain observational.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[27] STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion.

Shows: NK-specific Vegfa manipulation supported tumour promotion by a STAT5-deficient NK state rescued for survival with BCL2.

Does not show: Engineered survival rescue is not ordinary NK physiology; results oppose uniformly protective immune activation while identifying a specific pro-tumour pathway.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[28] The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.

Shows: Nlrp3 pathway deficiency increased liver metastatic growth with impaired IL18-dependent NK maturation and FasL function.

Does not show: Constitutive deficiency can affect development and other compartments; colonization and microbiome checks narrow but do not eliminate those alternatives.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[29] Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.

Shows: Microbiome and bile-acid changes altered hepatic CXCL16, NKT recruitment and NKT-dependent tumour control.

Does not show: Antibiotics are pleiotropic; NKT functional dependence supports liver-specific control rather than universal benefit of microbiome depletion.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[30] A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.

Shows: Enterocloster gavage, MAdCAM/integrin perturbation and IL17A neutralization linked antibiotic-induced regT17 trafficking to impaired checkpoint efficacy.

Does not show: Human serum MAdCAM prognosis does not isolate causality; results address therapy and microbial immune context rather than native transformation prevention.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[31] CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome.

Shows: Breast tumour models showed time-dependent CD4 subsets, while human CD8 and CD4 infiltrates associated in opposite directions with prognosis.

Does not show: The abstract does not document a selective depletion contrast; subgroup timing and prognostic association cannot establish causal human protection or uniform CD4 harm.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[32] Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies.

Shows: Rare dormant disseminated cells remained recognizable despite lower MHC; vaccination, TCR and CAR transfer eliminated them in tested systems.

Does not show: Scarce encounters explain incomplete surveillance. Treatment-mediated elimination does not establish routine sterilizing surveillance; original body was inaccessible in this examination.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[33] Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT.

Shows: SOX-dependent latency cells suppressed WNT and NK ligands through DKK1, coupling quiescence with evasion of clearance.

Does not show: Selected human-derived cell lines and imposed dissemination establish escape capability, not frequency of native human dormancy.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[34] Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin.

Shows: Resident CD8 deficiency and delayed depletion promoted outgrowth of occult epidermal melanomas; preformed resident memory protected independently of circulating cells.

Does not show: Transplantable antigenic melanoma remains a defined scope; about 40 percent macroscopic control and about 20 percent awakening after depletion show neither complete elimination nor exclusive immune dependence. Linked publisher correction metadata was retrieved but its substantive text was inaccessible; correction-specific impact remains unresolved.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID30742076. Subclaims: SC2, SC3.

[35] Adaptive immunity maintains occult cancer in an equilibrium state.

Shows: Primary chemical carcinogenesis demonstrated viable transformed cells held in prolonged adaptive-immune equilibrium, with editing on escape.

Does not show: Abstract-level examination supports the equilibrium distinction; exact depletion timing and doses were not independently verified in original Methods.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[36] CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer.

Shows: TNF and IFNgamma blockade broke dormancy and purified CD39-positive PD1-positive CD8 transfer prevented metastatic outgrowth.

Does not show: Original Methods select 54 patients already known to relapse; the infiltrate association was not independent in multivariable Cox analysis. Native untagged priming and timed cell/cytokine perturbations support mouse dormancy, and transfer left viable noncycling cells; clinical elimination remains unproved.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph16, 1:Results:paragraph18, 1:Results:paragraph23, 3:Methods:paragraph5, 3:Methods:paragraph7, 3:Methods:paragraph15, 3:Methods:paragraph21. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[37] Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy.

Shows: Syngeneic breast models identified different immune dependencies, including NK-sensitive proliferating cells and NK-resistant quiescent stem-like cells.

Does not show: Transplanted cell lines and model-specific dependencies narrow generalization; human estrogen-positive lifetime recurrence is background rather than direct prospective mediator evidence.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID37873211. Subclaims: SC2, SC3.

[38] Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis.

Shows: Alveolar macrophage depletion, cancer-cell TGFbetaRIII loss and receptor restoration linked resident macrophages to dormancy and awakening.

Does not show: This restrains established disseminated cells rather than eliminating them or preventing initial transformation; tumour promotion by other macrophage states remains compatible.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[39] Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.

Shows: T-cell conditional Arhgef1 deletion and platelet-specific COX1 deletion supported a TXA2-dependent immune mechanism for metastatic rejection and aspirin effects.

Does not show: Original Methods/Results include injected B16/LL2 dissemination and native MMTV-PyMT follow-up, T-cell Arhgef1 conditional deletion, platelet COX1 loss and TXA2-analogue reversal. Effects are epistatic and model-specific; human aspirin immune mediation and initial transformation prevention are not tested.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 5:Aspirin releases T cells from suppression by TXA2:paragraph0, 5:Aspirin releases T cells from suppression by TXA2:paragraph1, 6:Platelet COX-1 suppresses anti-metastatic immunity:paragraph0, 6:Platelet COX-1 suppresses anti-metastatic immunity:paragraph1, 8:Methods:paragraph0, 8:Methods:paragraph1, 8:Methods:paragraph2. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[40] Cell Competition Shapes Metastatic Latency and Relapse.

Shows: SPARC depletion had opposite effects before dissemination and after lung extravasation, demonstrating a nonexclusive cell-competition route to latency and relapse.

Does not show: Human renal-cancer subclone associations do not prove intervention efficacy; intrinsic competition can coexist with immune restraint.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[41] Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry.

Shows: USIDNET showed excess cancer mainly from lymphoma, without significant increases in common lung, colon, breast or prostate malignancies.

Does not show: Registry ascertainment, genotype syndromes and infection differ from controls; absence of significant common-solid excess constrains uniform protection rather than disproving all surveillance.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[42] Spectrum of cancer risk among US solid organ transplant recipients.

Shows: Linked US transplant registries showed infection-related and several unrelated cancers elevated after transplantation.

Does not show: Organ-specific underlying disease, surveillance and drugs are competing causes; early liver cancers can predate transplant and are not new transformation events.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[43] Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study.

Shows: Australian transplant failure comparisons found lower NHL, lip cancer and melanoma after immunosuppression reduction while several kidney-failure-associated cancers remained elevated.

Does not show: Original Methods exclude the first three months of each period, leaving 7809 analysable patients from 8173 enrolled. HPV-associated site reductions were not significant in adjusted comparisons. Graft failure changes dialysis/exposures; melanoma is not a proven virus-caused cancer, and persistent risks do not exclude earlier immune effects.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph4, 2:Results:paragraph0, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph9. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[44] Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency?

Shows: Australian primary-immunodeficiency registry linkage found a narrow excess of lymphoma, leukemia and stomach cancer.

Does not show: Small site-specific counts, infection and registration selection limit generalized inference; antibody and T-cell defects are not interchangeable surveillance instruments.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[45] Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population.

Shows: Baseline peripheral lymphocyte cytotoxicity predicted lower subsequent cancer incidence in a Japanese eleven-year cohort.

Does not show: Sex-specific estimates were imprecise and confounding remains; peripheral isotope-release activity is not directly measured tumour-specific elimination.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[46] Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance.

Shows: NKG2D haplotypes associated with cytotoxicity and cancer risk within the earlier Japanese cohort.

Does not show: Nested sampling shares the source cohort; linkage and pleiotropy preclude treating this as a validated causal genetic instrument. An unidentified erratum remains unresolved.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC1.

[47] Risk of cancers during interrupted antiretroviral therapy in the SMART study.

Shows: Randomized ART interruption increased AIDS-defining cancers, partly mediated by CD4 and HIV RNA, without a clear non-AIDS-defining difference.

Does not show: The intervention jointly changes virus suppression and immune function; it supports clinical infection-linked prevention rather than uniquely isolating transformed-cell recognition.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[48] Cancer risks after solid organ transplantation and after long-term dialysis.

Shows: Danish and Swedish transplant and dialysis registries reproduced a restricted set of elevated cancers.

Does not show: Dialysis-associated biology and surveillance can explain part of the overlap; independent geography does not remove the shared immune-deficiency exposure confounding.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[49] Pancreatic cancer among solid organ transplant recipients in the United States.

Shows: US transplant recipients had modestly elevated pancreatic cancer incidence, especially localized head lesions and liver recipients.

Does not show: Imaging detection, diabetes and organ-specific care confound attribution; this overlaps the US transplant-registry programme and is not an independent immune experiment.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[50] Risk of Colorectal Cancer After Solid Organ Transplantation in the United States.

Shows: US colorectal cancer excess was proximal and concentrated in underlying disease and drug strata; a tacrolimus/mycophenolate kidney subgroup lacked excess.

Does not show: Site and regimen specificity oppose uniform risk; conditional absence of excess does not prove immune irrelevance, and source patients overlap other transplant reports.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[51] No excess risk of follicular lymphoma in kidney transplant and HIV-related immunodeficiency.

Shows: Australian transplant/HIV cohorts showed large DLBCL excess but no significant follicular lymphoma excess.

Does not show: Follicular counts were small with wide intervals; subtype contrast supports restricted immunity/infection effects rather than a universal lymphoma mechanism.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[52] Merkel Cell Carcinoma and Immunosuppression, UV Radiation, and Merkel Cell Polyomavirus.

Shows: Registry and case-series synthesis estimated MCC burden attributable to immunosuppressing conditions, UV and polyomavirus.

Does not show: Small population fractions for rare immunodeficiency do not measure immunity's general protective effect; UV and viral attributable fractions overlap and cannot be summed.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[53] Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study.

Shows: Swedish HPV vaccination cohorts showed reduced genital warts, strongest when vaccination began young.

Does not show: The measured endpoint is genital warts, not invasive cancer or CIN; it is an exposure/control lead and cannot carry cancer prevention on its own.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[54] The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.

Shows: English age-eligible HPV vaccine cohorts had large reductions in cervical cancer and CIN3 after policy/screening adjustments.

Does not show: The mediator is infection prevention, not direct recognition of transformed cells; age-period effects and screening remain natural-experiment limitations.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[55] Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial.

Shows: Finnish follow-up of vaccinated trial cohorts found no HPV-positive invasive cancers versus seventeen controls.

Does not show: Controls combine randomized placebo and population cohorts; few events yield a very wide efficacy interval. Infection blockade is not transformed-cell surveillance alone.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[56] Improved survival with ipilimumab in patients with metastatic melanoma.

Shows: Randomized CTLA4 blockade improved overall survival in metastatic melanoma versus gp100 vaccine.

Does not show: Engineered checkpoint release demonstrates clinical control capacity, with substantial immune toxicity; it does not establish routine prevention in untreated hosts. An unidentified erratum needs qualification.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC2.

[57] Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

Shows: Sipuleucel-T improved prostate-cancer overall survival in a placebo-controlled trial but did not change objective progression time.

Does not show: Immune response and survival are not interchangeable with progression or mediation; the treatment is engineered and not ordinary surveillance.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[58] Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

Shows: Randomized PD1 blockade improved survival, response and progression outcomes over docetaxel in squamous NSCLC.

Does not show: Open-label treatment and previously treated disease narrow scope; receptor blockade provides targeted causal capacity without proving natural emergence prevention.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[59] Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Shows: Nivolumab improved overall survival in nonsquamous NSCLC despite an initially shorter median progression-free survival.

Does not show: Long-term tail and medians differ; established treated tumours are not nascent transformed-cell emergence, and clinical benefit does not alone prove every mediator step.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[60] Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma.

Shows: CheckMate067 ten-year follow-up showed durable survival benefit for nivolumab regimens versus ipilimumab.

Does not show: Original Methods identify 945 randomized patients and powered nivolumab-containing versus ipilimumab comparisons; combination versus nivolumab and melanoma-specific survival were descriptive/post hoc. Three-year landmark survivors are selected after treatment, and survival is not verified sterilizing clearance.

Access/status: Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 2:Results:paragraph0, 2:Results:paragraph18. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[61] Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study.

Shows: Adjuvant pembrolizumab improved distant-metastasis-free and recurrence-free survival after stage IIB/IIC melanoma resection.

Does not show: This causally restrains residual-disease outgrowth, not the first transformed cell; survival benefit and elimination of every dormant cell are not established by these endpoints.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[62] Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study.

Shows: Randomized CD19 CAR-T liso-cel improved event-free and progression-free survival over standard care in relapsed/refractory LBCL.

Does not show: Unadjusted overall-survival confidence intervals included no effect, with extensive crossover; adjusted estimates are model-dependent. Engineered antigen recognition supports control capacity.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[63] Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial.

Shows: ACTIV EGFRvIII vaccine added to temozolomide did not improve overall survival in the prespecified minimal-residual-disease glioblastoma population.

Does not show: A failed antigen/vaccine regimen constrains general treatment sufficiency, not the existence of immune tumour control in other contexts.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[64] Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma.

Shows: Adding T-VEC to pembrolizumab failed the randomized progression and overall-survival comparisons despite numerical response increases.

Does not show: Incremental combination failure is not failure of the active checkpoint backbone or proof against immune surveillance.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[65] Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor > 1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial.

Shows: GM2 vaccination failed relapse-free and overall-survival benefit; an early survival harm signal led to stopping.

Does not show: Later overall-survival intervals included no effect. Antibody induction is not proof of beneficial transformed-cell killing or a sufficient clinical endpoint.

Access/status: Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

Documentary record

Every grade on this site is reproducible from its record. The files below are the posted edition exactly as assessed.

• SHA256.txt
• codex-correction-provenance.json
• consensus-addendum.md
• consensus-validation.json
• edition-approval-audit.json
• immune-surveillance-cancer.review.md
• immune-surveillance-cancer.scorecard.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt

Sources: 65 · load-bearing claims: 69 · verified: 69 · unverified: 0 · contradicted: 0 · schema 5.3