Fig. 1

Schematic representation of cGAS/STING signaling in MICs. cGAS is a cytosolic PRR that recognizes and cleaves cytosolic dsDNA into CDN called cGAMP. The cytosolic dsDNA can be self-derived, including the mitochondrial DNA, produced during ER and genotoxic stress and mitochondrial stress and death. Also, MICs can get other cells’ DNA by phagocytosis, exosomes, and EVs along with pathogens. STING by serving as an adapter protein recognizes cGAMP. In addition to the cGAS-derived cGAMP, MICs can uptake extracellular cGAMP expelled from cancer cell in TIME through different transporters. This induces STING ERGIC movement. ERGIC localized STING interacts with the phosphorylated IRF8 (IRF8 phosphorylation occurs as a result dsDNA recognition by cGAS/STING signaling pathway). This interaction induces STING polymerization and its interaction with TBK1 and TRAF6. The interaction between STING and TBK1 induces STING phosphorylation. The STING-bound phosphorylated TBK1 induces IRF3 phosphorylation. Phosphorylated IRF3 induces transcription of ISGs, including type 1 IFN genes. Hence, cGAS/STING/IRF8/TBK1/IRF3 axis is critical to produce type 1 IFNs and propagate type 1 IFN-mediated immune response, including the antitumor immunity. On the other hand, TBK1-mediated TRAF6 activation is critical for another canonical cGAS/STING signaling pathway involving NF-κB-dependent pro-inflammatory immune response. Thus, regulated cGAS/STING signaling critically maintains immune homeostasis and helps to clear cancer cells, whereas its dysregulation causes chronic inflammation that may lead to cancer development. Kindly see the text for details