Extracellular cGAMP in health and disease

The cGAS-STING signaling pathway is a crucial component of the innate immune system that detects aberrant cytosolic DNA, such as that derived from viruses or damaged cells, to activate downstream immune responses. Within this pathway, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) serves as the essential second messenger linking DNA sensing to immune activation. Upon recognition of cytosolic DNA, cGAS synthesizes cGAMP, whose unique "mixed linkage" structure enables efficient binding to and activation of the STING protein on the endoplasmic reticulum, thereby inducing type I interferons and inflammatory cytokines. This review details cGAMP's biosynthesis, structural characteristics, and transport mechanisms, including efflux via ABCC1 and uptake by SLC19A1, underscoring its role as an intercellular "immune messenger." It also explores the dual functions of cGAMP in antiviral and antitumor immunity as well as in autoimmune and aging-related diseases, where it can either enhance immune defense or promote chronic inflammation. Therapeutically, cGAMP has been investigated as a vaccine adjuvant, a target for synthesis or degradation enzymes, and in nanoparticle-based delivery systems. However, challenges regarding its stability, delivery efficiency, and immunotoxicity remain, and future research should focus on real-time monitoring and tissue-specific modulation to advance cGAMP-based precision immunotherapeutics.