Cell子刊：武汉大学钟波/林丹丹揭示巨噬细胞通过维持Treg细胞存活，促进肺癌进展

Core Viewpoint - The study reveals a mechanism by which the STING-CD38 signaling axis in macrophages promotes the survival of regulatory T cells (Tregs) and accelerates the progression of non-small cell lung cancer (NSCLC) driven by KRAS mutations, providing insights into the limited efficacy of STING agonists in clinical settings [2][3][6]. Group 1 - The STING-CD38 signaling axis in macrophages depletes NAD+ in the tumor microenvironment, thereby promoting Treg survival and creating an immunosuppressive state that facilitates tumor progression [3][4]. - In a KRAS G12D-driven NSCLC mouse model, STING activation in macrophages was found to enhance Treg survival and accelerate NSCLC progression [4][6]. - Mechanistic studies indicate that STING-mediated NF-κB activation upregulates CD38 in Siglec-F low macrophages, leading to the hydrolysis of extracellular NAD+ in the tumor microenvironment [5][6]. Group 2 - Genetic knockout of STING or CD38, or treatment with CD38 inhibitors, restores NAD+ levels, induces Treg apoptosis via the ART2-P2RX7 signaling axis, and enhances anti-tumor CD8+ T cell responses [6][9]. - Importantly, CD38 inhibitors can increase the sensitivity of NSCLC mice to low-dose anti-CTLA4 therapy, suggesting a potential therapeutic strategy for overcoming resistance in immune checkpoint blockade (ICB) [6][9].