Gao Yu, Liang Yusheng, Yu Weize, Tan Xiaoming, Zhuang Gaojian, Li Bing, Huang Jiayi, Zheng Jinghao, Yang Xuanqi, Wen Leyun, Sun Lingling, Zhang Yuan
Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital. No. 35, Yinquan North Road, Qingcheng District, Qingyuan, 511518, Guangdong, China.
College of Pharmacy, Dali University, No. 22, Wanhua Road, Xiaguan Town, Dali Yunnan, 671000, China.
Med Oncol. 2025 May 28;42(7):223. doi: 10.1007/s12032-025-02773-7.
Tumor microenvironment (TME) plays a pivotal role in immunotherapy, especially in immune checkpoint inhibitors (ICIs) therapy, but how tumor cells and immune cells cross-talk with each other remains elusive. Thus, exploring the mechanisms is of urgent needs. Connexin 43 (Cx43) is a key gap junction (GJ) protein, which allows tumor cells and immune cells to interact. In this study, we systematically investigated the function of Cx43 in response to ICIs and observed that Cx43 promoted the activation of CD8 T cells by mediating the transfer of cyclic GMP-AMP (cGAMP) from tumor cells to macrophages, thereby increasing the sensitivity to anti-PD-1 therapy. In addition, the silencing of Cx43 significantly inhibited the activation of the cGAS-STING signaling pathway, leading to polarization of macrophages into tumor-associated macrophages (TAMs) and resistance to ICI treatment. Therefore, Cx43/GJ-mediated signaling between tumor cells and macrophages not only enhances CD8 T-cell immune responses but also provides a new theoretical basis and research direction for improving ICI efficacy.
肿瘤微环境（TME）在免疫治疗中起着关键作用，尤其是在免疫检查点抑制剂（ICI）治疗中，但肿瘤细胞与免疫细胞如何相互作用仍不清楚。因此，探索其机制迫在眉睫。连接蛋白43（Cx43）是一种关键的间隙连接（GJ）蛋白，它使肿瘤细胞与免疫细胞能够相互作用。在本研究中，我们系统地研究了Cx43在ICI反应中的功能，观察到Cx43通过介导环磷酸鸟苷-腺苷酸（cGAMP）从肿瘤细胞向巨噬细胞的转移来促进CD8 T细胞的活化，从而提高对抗PD-1治疗的敏感性。此外，Cx43的沉默显著抑制了cGAS-STING信号通路的活化，导致巨噬细胞极化为肿瘤相关巨噬细胞（TAM）并产生对ICI治疗的抗性。因此，Cx43/GJ介导的肿瘤细胞与巨噬细胞之间的信号传导不仅增强了CD8 T细胞的免疫反应，还为提高ICI疗效提供了新的理论基础和研究方向。
