Immune Regulation by Cytosolic DNA Sensors in the Tumor Microenvironment

SIMPLE SUMMARY: Cytosolic DNA sensors (CDSs), expressed in various types of immune and tumor cells, recognize double-stranded DNA (dsDNA) in the cytoplasm. These molecules are activated after the dsDNA recognition and initiate a cascade of events that culminate in the activation of innate and acquired immunity. CDSs were previously believed to recognize pathogen-derived DNA only. However, they can also respond to cytosolic DNA derived from tumor cells. This suggests that CDSs can be used as small-molecule inhibitor targets in combination with existing immunotherapies to enhance anti-tumor immune responses. This review summarizes current research on the mechanisms underlying CDSs, absent in melanoma 2 (AIM2), cyclic GMP-AMP synthase (cGAS), and stimulator of interferon genes (STING)—downstream signaling effectors of cGAS—in the tumor microenvironment. Furthermore, this review discusses the prospects for future anti-tumor immunotherapy strategies based on these molecules. ABSTRACT: cGAS and AIM2 are CDSs that are activated in the presence of cytosolic dsDNA and are expressed in various cell types, including immune and tumor cells. The recognition of tumor-derived dsDNA by CDSs in the cytosol of tumor-infiltrating dendritic cells (TIDCs) activates the innate and acquired immunity, thereby enhancing anti-tumor immune responses. STING is the downstream signaling effector of cGAS that induces type I interferon (IFN) signaling. Owing to their ability to activate TIDCs, STING agonists have been intratumorally injected in several clinical trials to enhance the anti-tumor immune response elicited by immune checkpoint antibodies. However, they have shown minimal effect, suggesting the importance of optimizing the dose and route of administration for STING agonists and deciphering other immune pathways that contribute to anti-tumor immune responses. Recent studies have revealed that AIM2 activity induces pro-tumor growth through multiple parallel pathways, including inhibition of STING-type I IFN signaling. Thus, AIM2 could be a potential molecular target for cancer immunotherapies. This review summarizes the current research on the roles of cGAS, STING, and AIM2 in immune cells and tumor cells in the tumor microenvironment and discusses the future prospects of anti-tumor treatment approaches based on these molecules.