Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity
Hao Zhou, Wenkan Zhang, Hengyuan Li, Fan Xu, Eloy Yinwang, Yucheng Xue, Tao Chen, Shengdong Wang, Zenan Wang, Hangxiang Sun, Fangqian Wang, Haochen Mou, Minjun Yao, Xupeng Chai, Jiahao Zhang, Mohamed Diaty Diarra, Binghao Li, Changqing Zhang, Junjie Gao, Zhaoming Ye
Abstract
Bone is one of the most common sites of tumor metastases. During the last step of bone metastasis, cancer cells colonize and disrupt the bone matrix, which is maintained mainly by osteocytes, the most abundant cells in the bone microenvironment. However, the role of osteocytes in bone metastasis is still unclear. Here, we demonstrated that osteocytes transfer mitochondria to metastatic cancer cells and trigger the cGAS/STING-mediated antitumor response. Blocking the transfer of mitochondria by specifically knocking out mitochondrial Rho GTPase 1 ( Rhot1 ) or mitochondrial mitofusin 2 ( Mfn2 ) in osteocytes impaired tumor immunogenicity and consequently resulted in the progression of metastatic cancer toward the bone matrix. These findings reveal the protective role of osteocytes against cancer metastasis by transferring mitochondria to cancer cells and potentially offer a valuable therapeutic strategy for preventing bone metastasis.