cGAMP

cGAMP stands for cyclic GMP-AMP, a small cyclic dinucleotide that acts as a second messenger in cellular signaling. In mammals, the most studied form is 2'3'-cGAMP, which contains a 2'-5' linkage and a 3'-5' linkage between GMP and AMP. Bacteria also produce related cyclic dinucleotides, including 3'3'-cGAMP, but the 2'3'-form is typically associated with the vertebrate cGAS-STING pathway.

Sensing cytosolic DNA: In mammalian cells, cytosolic DNA activates the enzyme cGAS (cyclic GMP-AMP synthase) to produce 2'3'-cGAMP. cGAMP binds to the adaptor protein STING (stimulator of interferon genes) on the endoplasmic reticulum membrane, triggering STING activation and translocation. This recruits downstream kinases such as TBK1 and IKKε, leading to phosphorylation of transcription factors IRF3 and NF-κB and the induction of type I interferons and other inflammatory genes.

Regulation and degradation: Extracellular cGAMP can be degraded by ENPP1, which helps regulate the magnitude and duration of the response. Bacteria possess diverse cGAMP synthases and phosphodiesterases that modulate signaling within prokaryotic immune pathways and can influence host–pathogen interactions when bacteria release CDN-containing molecules.

Applications and research: Because cGAMP activates STING, synthetic CDN analogs and derivatives are explored as immunotherapies and vaccine adjuvants to boost anti-tumor and antiviral responses. Ongoing research seeks to improve stability, delivery, and specificity while monitoring potential risks such as excessive inflammation or autoimmunity.