1. Connexin 43 Deficiency Confers Resistance to Immunotherapy in Lung Cancer via Inhibition of the Cyclic GMP‐AMP Synthase–Stimulator of Interferon Genes Pathway.
- Author
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Zhang, Yuan, Gao, Yu, Wang, Jie, Tan, Xiaoming, Liang, Yusheng, Yu, Weize, Deng, Zihua, Zhou, Jingjing, Ye, Zu, and Luo, Guoqing
- Subjects
CONNEXIN 43 ,IMMUNE checkpoint inhibitors ,LUNG cancer ,CANCER cells ,TREATMENT effectiveness - Abstract
Immune checkpoint inhibitors (ICIs), especially PD‐1 inhibitors, are among the first‐line therapeutic drugs for the treatment of advanced non‐small cell lung cancer (NSCLC). However, most patients are not sensitive to PD‐1 inhibitors, and prolonged exposure can lead to acquired resistance. Thus, it is urgent to elucidate the mechanism underlying the resistance of NSCLC to ICIs. Connexin 43 (Cx43) is a gap junction (GJ) protein that is important in therapeutic efficacy to ICIs. In this study, we observed that Cx43 in murine Lewis lung carcinoma (LLC) cells mediated cyclic GMP‐AMP (cGAMP) transfer to macrophages. Knockdown of Cx43 reduced T‐cell activation, leading to decreased sensitivity of LLC cells to anti‐PD‐1 therapy. The mechanism might be that knockdown of Cx43 in LLC cells promotes macrophages differentiation into pro‐tumour M2 type (TAM), thus activating the STING pathway in macrophages. These findings indicate that downregulation of Cx43 in LLC cells leads to immunotherapy resistance by negatively regulating the cGAS–STING pathway in macrophages. Therefore, Cx43/GJ‐mediated signal transmission between lung cancer cells and macrophages provides new insights for increasing immunotherapy sensitivity in NSCLC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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