Regulation and Function of the cGAS-STING Pathway: Mechanisms, Post-Translational Modifications, and Therapeutic Potential in Immunotherapy.

Abstract

Autoimmune diseases arise when the immune system attacks healthy tissues, losing tolerance for self-tissues. Normally, the immune system recognizes and defends against pathogens like bacteria and viruses. The cGAS-STING pathway, activated by pattern-recognition receptors (PRRs), plays a key role in autoimmune responses. The cGAS protein senses pathogenic DNA and synthesizes cGAMP, which induces conformational changes in STING, activating kinases IKK and TBK1 and leading to the expression of interferon genes or inflammatory mediators. This pathway is crucial in immunotherapy, activating innate immunity, enhancing antigen presentation, modulating the tumor microenvironment, and integrating into therapeutic strategies. Modulation strategies include small molecule inhibitors, oligonucleotide therapies, protein and antibody therapies, genetic and epigenetic regulation, cytokine and metabolite modulation, and nanoscale delivery systems. Post-translational modifications (PTMs) of the cGAS-STING pathway, such as phosphorylation, acetylation, ubiquitination, methylation, palmitoylation, and glycosylation, fine-tune immune responses by regulating protein activity, stability, localization, and interactions. These modifications are interconnected and collectively influence pathway functionality. We summarize the functions of cGAS-STING and its PTMs in immune and non-immune cells across various diseases, and explore potential clinical applications.