Cx43 mediates cross-talk of tumor cells and macrophage via cGAS-STING signaling.

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.