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

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机构： [1]Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China [2]Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China [3]College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China [4]Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co., Ltd., Shanghai 201318, China [5]Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No.507, Zhengmin Road, Shanghai 200433, China [6]Department of Thoracic Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China [7]Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan Province 610083, China [8]School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China [9]Department of Oncology, The Affiliated Dongnan Hospital of Xiamen University, Zhangzhou 363000, China [10]The 988th Hospital of Joint Logistic Support Force of PLA, Zhengzhou, Henan 450042, China [11]Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan 572013, China [12]Department of Respiratory Diseases, Xinqiao Hospital, Army Medical University, Chongqing 400037, China [13]Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing 100088, China [14]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA [15]Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China [16]Institute of Immunology, Third Military Medical University, Chongqing 400038, China [17]School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China [18]Blizard Institute, Barts and London School of Medicine and Dentistry, University of London, London E12AT, UK [19]Institute of Molecular and Cell Biology (IMCB) & Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(*) STAR), Singapore 138668, Singapore [20]Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138668, Singapore [21]Chongqing Advanced Pathology Research Institute, Jinfeng Laboratory, Chongqing 401329, China [22]Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China

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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.Copyright © 2025 Elsevier Inc. All rights reserved.

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大类 | 1 区

医学

小类 | 1 区细胞生物学 1 区肿瘤学

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大类 | 1 区

医学

小类 | 1 区细胞生物学 1 区肿瘤学

第一作者：

第一作者机构： [1]Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China [2]Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China

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通讯作者：

通讯机构： [1]Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China [2]Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China [19]Institute of Molecular and Cell Biology (IMCB) & Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(*) STAR), Singapore 138668, Singapore [20]Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138668, Singapore [21]Chongqing Advanced Pathology Research Institute, Jinfeng Laboratory, Chongqing 401329, China [22]Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China

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