Super-high tumor mutational burden predicts complete remission following immunotherapy: from Peto’s paradox to druggable cancer hallmark

Somatic 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.