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

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

Cancer Cell

10.1016/j.ccell.2025.03.036

https://doi.org/10.1016/j.ccell.2025.03.036

Jia-Nan Cheng, Zheng Jin, Chunxia Su, Tao Jiang, Xiaobin Zheng, Jinming Guo, Xingyi Li, Han Chu, Jia Jia, Qin Zhou, Xiaofang Ding, Yiwen Zhang, Shouxia Xu, Fancong Dong, Qiao Zhang, Xinxin Yang, Tao Yang, Xiaoming Cheng, Haoran Zha, Degao Chen, Yisong Y. Wan, Xindong Liu, Lilin Ye, Haidong Tang, Alistair L.J. Symonds, Qi-Jing Li, Qingzhu Jia, Bo Zhu

24 April 2025

Cheng, J.-N., Jin, Z., Su, C., Jiang, T., Zheng, X., Guo, J., Li, X., Chu, H., Jia, J., Zhou, Q., Ding, X., Zhang, Y., Xu, S., Dong, F., Zhang, Q., Yang, X., Yang, T., Cheng, X., Zha, H., et al. (2025). Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts. Cancer Cell, 43(6), 1093–1107. https://doi.org/10.1016/j.ccell.2025.03.036

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the National Research Foundation (NRF) Singapore - National Research Foundation Investigatorship
Grant Reference no. : NRF-NRFI09-0009

© 2025 Elsevier B.V. This manuscript version is made available under the CC BY-NC-ND. This is an Accepted Manuscript of an article published by Elsevier in Cancer Cell, available at https://doi.org/10.1016/j.ccell.2025.03.036

https://oar.a-star.edu.sg/communities-collections/articles/23201

1535-6108

Institute of Molecular and Cell Biology