Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts

Jia-Nan Cheng¹, Zheng Jin², Chunxia Su³, Tao Jiang³, Xiaobin Zheng⁴, Jinming Guo⁵, Xingyi Li⁶, Han Chu¹, Jia Jia¹, Qin Zhou¹, Xiaofang Ding¹, Yiwen Zhang¹, Shouxia Xu⁷, Fancong Dong⁸, Qiao Zhang⁹, Xinxin Yang¹, Tao Yang¹⁰, Xiaoming Cheng¹¹, Haoran Zha¹², Degao Chen¹, Yisong Y Wan¹³, Xindong Liu¹⁴, Lilin Ye¹⁵, Haidong Tang¹⁶, Alistair L J Symonds¹⁷, Qi-Jing Li¹⁸, Qingzhu Jia¹⁹, Bo Zhu²⁰

Affiliations

¹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China.
² College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China; Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co., Ltd., Shanghai 201318, China.
³ Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No.507, Zhengmin Road, Shanghai 200433, China.
⁴ Department of Thoracic Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China.
⁵ College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
⁶ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan Province 610083, China.
⁷ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
⁸ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Department of Oncology, The Affiliated Dongnan Hospital of Xiamen University, Zhangzhou 363000, China.
⁹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; The 988th Hospital of Joint Logistic Support Force of PLA, Zhengzhou, Henan 450042, China.
¹⁰ Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan 572013, China.
¹¹ Department of Respiratory Diseases, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
¹² Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing 100088, China.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
¹⁵ Institute of Immunology, Third Military Medical University, Chongqing 400038, China.
¹⁶ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
¹⁷ Blizard Institute, Barts and London School of Medicine and Dentistry, University of London, London E12AT, UK.
¹⁸ Institute of Molecular and Cell Biology (IMCB) & Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138668, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138668, Singapore. Electronic address: li_qijing@imcb.a-star.edu.sg.
¹⁹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China. Electronic address: qingzhu.jia@tmmu.edu.cn.
²⁰ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Advanced Pathology Research Institute, Jinfeng Laboratory, Chongqing 401329, China; Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China. Electronic address: bo.zhu@tmmu.edu.cn.

PMID: 40280123
DOI: 10.1016/j.ccell.2025.03.036

Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts

Jia-Nan Cheng et al. Cancer Cell. 2025.

. 2025 Jun 9;43(6):1093-1107.e9.

doi: 10.1016/j.ccell.2025.03.036. Epub 2025 Apr 24.

Authors

Affiliations

¹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China.
² College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China; Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co., Ltd., Shanghai 201318, China.
³ Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No.507, Zhengmin Road, Shanghai 200433, China.
⁴ Department of Thoracic Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China.
⁵ College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
⁶ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan Province 610083, China.
⁷ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
⁸ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Department of Oncology, The Affiliated Dongnan Hospital of Xiamen University, Zhangzhou 363000, China.
⁹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; The 988th Hospital of Joint Logistic Support Force of PLA, Zhengzhou, Henan 450042, China.
¹⁰ Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan 572013, China.
¹¹ Department of Respiratory Diseases, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
¹² Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing 100088, China.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
¹⁵ Institute of Immunology, Third Military Medical University, Chongqing 400038, China.
¹⁶ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
¹⁷ Blizard Institute, Barts and London School of Medicine and Dentistry, University of London, London E12AT, UK.
¹⁸ Institute of Molecular and Cell Biology (IMCB) & Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138668, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138668, Singapore. Electronic address: li_qijing@imcb.a-star.edu.sg.
¹⁹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China. Electronic address: qingzhu.jia@tmmu.edu.cn.
²⁰ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Advanced Pathology Research Institute, Jinfeng Laboratory, Chongqing 401329, China; Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China. Electronic address: bo.zhu@tmmu.edu.cn.

PMID: 40280123
DOI: 10.1016/j.ccell.2025.03.036

Abstract

Bone metastatic lesions typically associate with suboptimal responses to immune checkpoint blockade (ICB) therapies. In this study, we observed that across multiple clinical cohorts and a variety of mouse models, the presence of osseous metastases induces ICB resistance in extraosseous tumors. Mechanistically, this long-distance communication is mediated by osseous tumor-conditioned osteoclasts producing osteopontin (OPN). Through circulation, OPN reprograms the extraosseous tumor microenvironment and impairs T cell recruitment and differentiation of CD8⁺TCF1⁺ precursor cells, an essential population for ICB efficacy. In mice, ICB responsiveness is restored by αRANKL blockade of osteoclastogenesis, neutralization of OPN in circulation, or tissue-specific depletion of OPN in osteoclasts. Both the mode of action and therapeutic benefit were validated in clinical cohorts with the αRANKL-ICB combinatory regimen. These findings establish bone as a specific immunoregulatory organ exploited by tumor metastasis and suggest osteoclastogenesis as a promising target to improve ICB prognosis in patients with bone metastasis.

Keywords: bone metastasis; denosumab; immunotherapy; osteoclast; osteopontin.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts

Affiliations

Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials