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.