Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers

Cancer in younger adults is rising globally, with notable birth-cohort effects. This epidemiological shift underscores the urgent need to accelerate the identification of novel causes and underlying biological networks, with the aim of translating these insights into prevention and interception strategies. In this perspective, we revisit the major milestones in the discovery of cancer causes and outline challenges that hinder progress. To address these challenges, we advocate closer integration of epidemiologic and mechanistic studies and propose three interconnected frameworks that extend current epidemiologic approaches: a tissue ecosystem-anchored framework for cancer cause discovery, a biological state-based framework for precision cancer risk assessment, and a dynamic framework to characterize cancer preventability. This roadmap aims to stimulate conceptual, resource, and methodological advances to accelerate cancer etiology research and prevention in the era of rising early-onset cancers.