ArticleJournal for immunotherapy of cancer2025
Super-high tumor mutational burden predicts complete remission following immunotherapy: from Peto's paradox to druggable cancer hallmark.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- UBE2A as a prognostic indicator across human cancers: Insights from multi‑omics and immune landscape analyses.Molecular medicine reports · 2026Article
- Case Report: Metastatic melanoma with initial ctdna decline and radiographic response during self-directed antiparasitic use: treatment effect or spontaneous regression?Frontiers in oncology · 2026Article
Corrections and comments
- Erratum issued
Authors and funding
1 author.
Funding
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Abstract
backgroundThe somatic mutation theory predicts that cancer risk should scale proportionally with lifetime cell divisions; yet large-bodied and long-lived species exhibit lower-than-expected cancer incidence-a long-standing contradiction termed Peto's paradox. Resolving this paradox and clarifying how tumor mutational burden (TMB) shapes treatment response to immune-checkpoint inhibitor (ICI) therapy remain unmet needs in precision oncology.
methodsThis study analyzed three data streams: (1) human cancer incidence data from North American registries; (2) cancer mortality records for 110,148 mammals (191 species) linked to body mass, life expectancy, and cancer risk, and (3) >30,000 tumors profiled in three independent pan-cancer cohorts and clinical outcomes in >2,700 ICI-treated patients. A digital-medicine approach using 1,000 bootstraps was employed to generate digital randomized cohorts for internal validation, with clinicogenomic covariates matched to mirror real-world clinical features.
results(1) Both cancer incidence and mutational accumulation are age-coupled in humans (
conclusionsSomatic mutational accumulation emerges as a unifying determinant of cancer risk in human and non-human species, resolving Peto's paradox and redefining TMB as a clinically actionable cancer hallmark. Quantifying TMB stratifies immunotherapy efficacy dose-dependently, with super-high TMB predicting durable tumor eradication; thus, therapeutically boosting neoantigen load in low-TMB tumors may convert ICI non-responders to responders. By proposing a universal framework-"cancer disease continuum"-unified by mutational burden as a shared hallmark across tumor initiation, progression, and immunogenicity, this study recasts mutational burden as both a biological price of longevity and an Achilles' heel exploitable for durable, complete tumor remission in personalized medicine.
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