Extracellular vesicles as mediators of exercise effects in cancer

Abstract Exercise is a well-established non-pharmacological intervention in oncology, consistently associated with reduced cancer risk and improved disease outcomes. Yet, the molecular mechanisms through which physical activity exerts its anticancer effects remain incompletely understood. Extracellular vesicles (EVs) released in response to exercise have emerged as promising candidate mediators of these effects, acting as intercellular communication carriers that transport bioactive molecules modulating the tumor microenvironment and capable of interacting with distant tissues. The composition of EV cargo is highly sensitive to exercise modality, intensity, and physiological status. Aerobic and resistance exercise each elicit different EV molecular signatures that converge on key processes, including angiogenesis, immune surveillance, metabolic reprogramming, and inflammatory signaling. Preclinical data indicates that EVs obtained from exercised animals reduce tumor cell viability, impair proliferation and migration, induce apoptosis, and slow tumor progression in sedentary animals, positioning EVs as key mediators of exercise-induced tumor suppression. However, the contribution of different cellular origins, exercise protocol specificity, as well as biological sex to EV composition and anticancer function remain largely unresolved, limiting mechanistic interpretation and clinical translation. This review synthetizes the current evidence on the role of EVs released in response to exercise in cancer development and progression, identifies the key biological and methodological gaps impeding progress, and evaluates the translational challenges that must be overcome to harness their therapeutic potential in oncology.