Exercise and antitumor immunity: molecular signaling, immune dynamics, and remodeling of the tumor microenvironment

Exercise is increasingly being investigated as a host-directed physiological intervention capable of modulating cancer-related immune, metabolic, and vascular processes. Epidemiological studies associate higher levels of habitual physical activity with lower cancer risk and improved outcomes in several patient populations, whereas preclinical studies have identified candidate mechanisms involving catecholamines, cytokines, metabolites, extracellular vesicles, immune-cell trafficking, and tumor perfusion. However, the strength of evidence varies substantially across mechanisms and experimental systems. Acute exercise transiently mobilizes natural killer cells and cytotoxic T cells, whereas repeated exercise training may modify systemic inflammation, metabolic homeostasis, and vascular function. Evidence from selected animal models further suggests that these responses can alter immune-cell infiltration, tumor metabolism, and treatment responsiveness. By contrast, direct evidence of sustained remodeling of the human tumor microenvironment remains limited. This review integrates molecular, cellular, and microenvironmental findings while distinguishing established observations from model-dependent mechanisms and proposed cross-tissue pathways. We also examine heterogeneity in exercise regimens, candidate response biomarkers, and priorities for mechanism-informed clinical trials. Standardized exercise reporting, temporally resolved biosampling, and paired systemic and tumor-level analyses are needed to determine when and in which patients exercise produces biologically meaningful antitumor effects.