身体活动通过多种机制降低癌症相关死亡率，包括肿瘤免疫微环境（TIME）重新编程。然而，生理干预是否以及如何促进抗肿瘤免疫仍然难以捉摸。在此，我们报告临床相关的自愿运动可促进肌肉源性细胞外囊泡（EV）相关的 miR-29a-3p 抑制患者和小鼠模型中的肿瘤细胞外基质（ECM），从而允许免疫细胞浸润和免疫治疗。从机制上讲，无偏见的筛查可识别 EV 相关的 miR-29a-3p，以响应休闲时间的体力活动或自愿锻炼。含有 MiR-29a-3p 的 EV 在肿瘤中积聚，并通过靶向 COL1A1 下调胶原蛋白组成。功能获得和丧失实验以及飞行时间细胞计数 (CyTOF) 表明，肌细胞分泌的 miR-29a-3p 可以促进抗肿瘤免疫。将免疫疗法与自愿运动或miR-29a-3p相结合可进一步增强抗肿瘤功效。临床上，miR-29a-3p 与 ECM 减少、T 细胞浸润增加以及对免疫治疗的反应相关。我们的工作揭示了 miR-29a-3p 对免疫治疗的预测价值，提供了运动诱导的抗癌免疫的机制见解，并强调了自愿运动在敏化免疫治疗中的潜力。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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 remain elusive. Here, we report that clinically relevant voluntary exercise promotes muscle-derived extracellular vesicle (EV)-associated miR-29a-3p for tumor extracellular matrix (ECM) inhibition in patients and mouse models, thereby permitting immune cell infiltration and immunotherapy. Mechanistically, an unbiased screening identifies EV-associated miR-29a-3p in response to leisure-time physical activity or voluntary exercise. MiR-29a-3p-containing EVs accumulate in tumors and downregulate collagen composition by targeting COL1A1. Gain- and loss-of-function experiments and cytometry by time of flight (CyTOF) demonstrate that myocyte-secreted miR-29a-3p promotes anti-tumor immunity. Combining immunotherapy with voluntary exercise or miR-29a-3p further enhances anti-tumor efficacy. Clinically, miR-29a-3p correlates with reduced ECM, increased T cell infiltration, and response to immunotherapy. Our work reveals the predictive value of miR-29a-3p for immunotherapy, provides mechanistic insights into exercise-induced anti-cancer immunity, and highlights the potential of voluntary exercise in sensitizing immunotherapy.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.