The Immune-Mutation Axis of Cancer Incidence: Insights from 30,000 TCR β Repertoires

Immunoediting posits that mutation and immunity jointly shape cancer evolution, yet their population-level interplay remains uncertain. Here we analyze T cell receptor (TCR) β repertoires from 30,000 individuals and find that TCR diversity, essential for recognizing and eliminating malignant cells, declines with age. This immune decline occurs 11 years later in females and coincides with their lower cancer incidence, suggesting a biological connection. To test this link, we formalize immunoediting as a quantitative model of carcinogenesis, relating the measured age-associated decline in TCR diversity to rising cancer incidence. We find that both mutational and immune processes shape cancer risk, with lower incidence in females attributable to delayed immune decline. Extending this analysis across subtypes uncovers structured patterns in cancer incidence that reflect the relative contributions of these processes. Cancers cluster along an emergent immune-mutation axis that aligns with known features of cancer biology and indicates convergent evolutionary dynamics. Together, our results establish a quantitative, population-level framework for immunoediting that connects direct measurements of immune competence to cancer risk, integrating the molecular mechanisms, evolutionary dynamics and incidence patterns of cancer to reveal a fundamental balance between mutation and immunity that underlies carcinogenesis.