Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity.

The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67(+) immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3(+) immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals. These findings link exercise training to cancer risk reduction by alleviating inflammation, decreasing immunosenescence, and improving the reservoirs of overall immunity for cancer prevention.