Strategies involving STING pathway activation for cancer immunotherapy: Mechanism and agonists

Recent studies have expanded the known functions of cGAS-STING in inflammation to a role in cancer due to its participation in activating immune surveillance. In cancer cells, the cGAS-STING pathway can be activated by cytosolic dsDNA derived from genomic, mitochondrial and exogenous origins. The resulting immune-stimulatory factors from this cascade can either attenuate tumor growth or recruit immune cells for tumor clearance. Furthermore, STING-IRF3-induced type I interferon signaling can enforce tumor antigen presentation on dendritic cells and macrophages and thus cross-prime CD8⁺ T cells for antitumor immunity. Given the functions of the STING pathway in antitumor immunity, multiple strategies are being developed and tested with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells to elicit immunostimulatory effects, either alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. Based on the canonical molecular mechanism of STING activation, numerous strategies for inducing mitochondrial and nuclear dsDNA release have been used to activate the cGAS-STING signaling pathway. Other noncanonical strategies that activate cGAS-STING signaling, including the use of direct STING agonists and STING trafficking facilitation, also show promise in type I interferon release and antitumor immunity priming. Here, we review the key roles of the STING pathway in different steps of the cancer-immunity cycle and characterize the canonical and noncanonical mechanisms of cGAS-STING pathway activation to understand the potential of cGAS-STING agonists for cancer immunotherapy.