2025年4月24日出版的《癌细胞》杂志发表了中国科学家的一项最新研究成果。来自第三军医大学的朱波研究组揭示了骨转移瘤通过产生骨桥蛋白的破骨细胞减少对检查点阻断免疫疗法的骨外反应。

在这项研究中，研究人员观察到，在多个临床队列和多种motheme模型中，骨转移的存在诱导骨外肿瘤的ICB抵抗。从机制上讲，这种长距离通信是由骨肿瘤条件下产生骨桥蛋白（OPN）的破骨细胞介导的。通过循环，OPN重新编程骨外肿瘤微环境，并损害T细胞募集和CD8⁺TCF1⁺前体细胞的分化，而CD8⁺TCF1⁺前体细胞是ICB疗效的重要群体。在小鼠中，通过αRANKL阻断破骨细胞生成、循环中OPN的中和或破骨细胞中OPN的组织特异性耗损，ICB反应性得以恢复。在αRANKL-ICB联合方案的临床队列中验证了作用方式和治疗效果。这些发现表明骨是肿瘤转移的特异性免疫调节器官，并提示破骨细胞生成是改善骨转移患者ICB预后的一个有希望的靶点。

据了解，骨转移病变通常与免疫检查点阻断（ICB）治疗的次优反应相关。

附：英文原文

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

Author: 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

Issue&Volume: 2025-04-24

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.

DOI: 10.1016/j.ccell.2025.03.036

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00137-0