Skeletal Muscle as a Trainable Anticancer Endocrine Organ: Integrating Myokines, Exercise-Derived Extracellular Vesicles, and Immunometabolic Reprogramming in Exercise Oncology

Exercise oncology has moved from epidemiological association to mechanistic science, yet contracting skeletal muscle is still treated in most oncological models as a bystander rather than as an active regulator of tumour biology. This review integrates evidence from prospective cohorts, controlled exercise trials, tumour-bearing animal models and human ex vivo serum and extracellular vesicle (EV) studies into a single three-level muscle-tumour crosstalk axis. At the first level, repeated contraction remodels the muscle secretome, releasing soluble myokines and EV cargo that act directly on neoplastic cells. At the second level, each exercise bout—and, cumulatively, its chronic repetition—reshapes systemic immunometabolic conditions: immune-cell trafficking, catecholamine and substrate availability, insulin signalling and low-grade inflammation. At the third level, these systemic changes converge on the tumour microenvironment, altering immune infiltration, vascular function, hypoxia, drug delivery and proliferative signalling. The same axis is supported in reverse by the consistent prognostic weight of sarcopenia and cancer cachexia. The 2025 CHALLENGE trial, which improved disease-free survival after adjuvant therapy for colon cancer, supplies the first survival-grade clinical evidence. The review closes with a mechanism-informed prescription framework and a ranked set of unresolved questions concerning EV standardisation, dose-response, tumour-type specificity and synergy with immunotherapy.