Chronic and non-canonical cGAS–STING activation: implications for health, disease, cancer, and emerging therapeutic opportunities

Immunotherapy has drawn attention in the current era; CAR T cells and STING agonists are emerging as novel approaches for cancer treatment. Advances in STING agonist development are ongoing, and many remain in the preclinical stage. At the same time, it is now clear that dysregulated or chronic activation of the cGAS–STING pathway contributes to a broad spectrum of human pathological conditions. Classically, cGAS, as a sensor of dsDNA, recognizes the cytoplasmic dsDNA and, due to the enzymatic activity, generates a di-nucleotide molecule as the 2′3′ cGAMP. 2′3′ cGAMP behaves as the natural activator of STING and further facilitates the downstream pathway via TBK1 to IRF-3 and NF-κB. Conventionally, this pathway is explored in the context of the antiviral immune response. The agonists of STING have a distinct role in immunotherapy, but the cGAS–STING pathway is also associated with other molecular mechanisms that deviate from its canonical pathway and activate its non-canonical pathway, which leads to different molecular patterns, and this is associated with many diseases and cancer survival. Here, we discussed the various pathways that regulate the cGAS–STING activation in chronic and non-canonical ways. Chronic and non-canonical pathways associated with human disease and cancer. We also discussed the therapeutic opportunities.