MITA/STING-driven CD38 induction in Siglec-F macrophages promotes regulatory T cell survival and non-small cell lung cancer progression.

Stimulator of interferon (IFN) genes (STING, also known as [mediator of IRF3 activation]) is a 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) receptor that activates type I IFN responses to inhibit tumorigenesis in tumor cells. However, STING agonists show limited antitumor clinical efficacy. Here, we demonstrate that STING in macrophages promotes the survival of regulatory T cells (Tregs) and the progression of non-small cell lung cancer (NSCLC) in KRas autochthonous NSCLC mouse models. Mechanistically, STING-mediated nuclear factor κB (NF-κB) activation upregulates CD38 in Siglec-F macrophages to hydrolyze extracellular nicotinamide adenine dinucleotide (NAD) in the tumor microenvironment (TME). Genetic deletion of STING or CD38, or pharmacological CD38 inhibition, restores NAD levels, triggers Treg apoptosis through the ART2-P2RX7 axis, and enhances antitumor CD8 T cell responses. Importantly, CD38 inhibition improves the efficacy of low-dose anti-CTLA4 therapy. These findings uncover a previously uncharacterized cGAMP-STING-CD38 axis in macrophages supporting Treg survival and NSCLC progression and highlight potential therapeutic strategies for immune checkpoint blockade (ICB)-resistant cancers.