Voluntary exercise sensitizes cancer immunotherapy via the collagen inhibition-orchestrated inflammatory tumor immune microenvironment
Zhiwen Luo,
Jie Mei,
Xianwen Wang,
Ruixin Wang,
Zhao He,
Yifat Geffen,
Xiaomeng Sun,
Xingyu Zhang,
Junying Xu,
Renwen Wan,
Xinting Feng,
Chunmeng Jiao,
Xiaoping Su,
Junming Sun,
Shiyi Chen,
Jiwu Chen,
Wenjun Mao,
Yunlong Yang,
Yaying Sun
Affiliations
Zhiwen Luo
Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Jie Mei
The First Clinical Medicine College, Nanjing Medical University, Nanjing 211166, China; Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing 211166, China; Corresponding author
Xianwen Wang
School of Biomedical Engineering, Anhui Medical University, Hefei 230032, Anhui, China
Ruixin Wang
Department of Cardiothoracic Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing 211166, China
Zhao He
Department of Cardiothoracic Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing 211166, China
Yifat Geffen
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Xiaomeng Sun
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Xingyu Zhang
Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Junying Xu
Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing 211166, China
Renwen Wan
Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Xinting Feng
Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Chunmeng Jiao
Guangdong Pharmaceutical University, Guangzhou 510006, China
Xiaoping Su
Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Medical University, Nanning 530021, Guangxi, China
Junming Sun
Laboratory Animal Center, Guangxi Medical University, Nanning 530021, Guangxi, China
Shiyi Chen
Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Jiwu Chen
Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Wenjun Mao
Department of Cardiothoracic Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing 211166, China; Corresponding author
Yunlong Yang
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Corresponding author
Yaying Sun
Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Corresponding author
Summary: 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.
