cGAS/cGAMP/STING signal propagation in the tumor microenvironment: Key role for myeloid cells in antitumor immunity.

Cyclic GMP-AMP synthase (cGAS), second messenger 2'3'-cyclic GMP-AMP (cGAMP) and stimulator of interferon genes (STING) are fundamental for sensing cytoplasmic double stranded DNA. Radiotherapy treatment induces large amounts of nuclear and mitochondrial DNA damage and results in the presence of DNA fragments in the cytoplasm, activating the cGAS/STING pathway. Triggering of the cGAS/STING pathway in the tumor microenvironment (TME) results in the production of type I interferons (IFNs). Type I IFNs are crucial for an effective antitumor defense, with myeloid cells as key players. Many questions remain on how these myeloid cells are activated and in which cells (tumor versus myeloid) in the TME the signaling pathway is initiated. The significance of cGAS/STING signaling in the onco-immunology field is being recognized, emphasized by the frequent occurrence of mutations in or silencing of genes in this pathway. We here review several mechanisms of cGAS/STING signal propagation in the TME, focusing on tumor cells and myeloid cells. Cell-cell contact-dependent interactions facilitate the transfer of tumor-derived DNA and cGAMP. Alternatively, transport routes via the extracellular space such as extracellular vesicles, and channel-mediated cGAMP transfer to and from the extracellular space contribute to propagation of cGAS/STING signal mediators DNA and cGAMP. Finally, we discuss regulation of extracellular cGAMP. Altogether, we provide a comprehensive overview of cGAS/cGAMP/STING signal propagation from tumor to myeloid cells in the TME, revealing novel targets for combinatorial treatment approaches with conventional anticancer therapies like radiotherapy.