STING/MITA-CD38 axis in macrophages supports regulatory T cell survival and NSCLC progression.
Mediator of IRF3 activation (MITA, also known as STING) is a cyclic GMP-AMP (cGAMP) receptor that activates type I interferon responses to inhibit tumorigenesis in tumor cells. However, the MITA agonists have limited antitumor efficacy in clinical trials. Here we show that MITA in macrophages promotes the survival of regulatory T cell (Treg) in the tumor microenvironment (TME) and the progression of non-small cell lung cancer (NSCLC) in the KRasG12D autochthonous NSCLC mouse models. Mechanistically, MITA-mediated activation of NF-?B upregulates CD38 in monocyte-derived macrophages (MDMs) that metabolizes nicotinamide adenine dinucleotide (NAD) into niacinamide (NAM) and ADP-ribose in the TME. Inhibition of CD38 enzymatic activity or deletion of MITA or CD38 alone or simultaneously in macrophages results in the accumulation of NAD that induces apoptosis of Treg via the ART2-P2RX7 axis and enhances antitumor CD8+ T-cell responses in the TME. Importantly, pharmacological inhibition of CD38 sensitizes mice to the low-dose anti-CTLA4 therapy in the KRasG12D autochthonous NSCLC mouse models. These findings uncover a previously uncharacterized cGAMP-MITA-CD38 axis in MDMs that supports Treg survival and NSCLC progression and highlight potential therapeutic strategies for immune checkpoint blockade (ICB)-resistant cancers. Overall design: Comparative gene expression profiling analysis of single cell RNA-seq data in immune cells sorted from tumor-burdened lungs of WTKL  and LYZKL mice {transferring the bone marrow cells from Tmem173fl/fl,  Tmem173fl/fl;Lyz2-Cre mice into the lethally irradiated KrasLSL-G12D/+Lkb1fl/fl (KL)  mice}.