Voluntary exercise sensitizes cancer immunotherapy via collagen degradation-orchestrated inflammatory tumor immune microenvironment

Physical activity reduces cancer-associated mortality through multiple mechanisms, including tumor immune microenvironment (TIME) reprogramming. However, whether and how physiological interventions promote anti-tumor immunity and immunotherapy remains elusive. Here we report that clinically relevant voluntary exercise promotes muscle-derived exosomal miR-29a-3p for extracellular matrix (ECM) degradation in patients and mouse models with multiple types of cancer, thereby permitting immune cell infiltration and immunotherapy. Mechanistically, an unbiased screening identified exercise-responsive exosomal miR-29a-3p that targets tumor cell and cancer associated fibroblasts to downregulate COL1A1 and reduce ECM. State-of-the-art techniques including cytometry by time-of-flight (CyTOF) demonstrated miR-29a-3p-induced TIME remodeling and immune cell infiltration. Combining immunotherapy with voluntary exercise or miR-29a-3p further increased the anti-tumor efficacy in preclinical models. Clinically, miR-29a-3p was correlated with degraded ECM and T-cell infiltration in various cancer types in patients, and correlated with immunotherapy responders. Our work reveals the novel predictive value of miR-29a-3p for immunotherapy, provides mechanistic insights into exercise-promoted anti-cancer immunity, and highlights the therapeutic potential of voluntary exercise in immunotherapy. To identity differentially expressed miRNAs in circulating extracellular vesicles in serum from NSCLC patients with and without exercise habit, total RNA of circulating extracellular vesicles were submitted for miRNA-seq .