Cyclic GMP-AMP synthase–stimulator of interferon genes signaling pathway (cGAS-STING signaling pathway)

The **cyclic GMP–AMP synthase–stimulator of interferon genes signaling pathway** (**cGAS-STING signaling pathway**) is a central component of the innate immune system that detects cytosolic double-stranded DNA from pathogens or damaged host cells. Upon sensing DNA in the cytoplasm—an abnormal event usually associated with infection, cellular stress, tumorigenesis, or mitochondrial dysfunction—the enzyme **cGAS** synthesizes cyclic GMP–AMP (**cGAMP**), which acts as a second messenger. **cGAMP** binds to and activates **STING**, an adaptor protein located on the endoplasmic reticulum membrane. Activated STING then triggers downstream phosphorylation events leading to nuclear translocation of transcription factors such as IRF3 and subsequent induction of type I interferons and other inflammatory cytokines. This rapid innate immune response is crucial for antiviral defense but also plays roles in antitumor immunity by promoting immunosurveillance against cancer cells. However, dysregulation—either excessive activation by self-DNA or chronic stimulation—can result in harmful sterile inflammation implicated in autoimmune diseases, tissue degeneration, cardiovascular injury after ischemia-reperfusion events, and even promote aspects of carcinogenesis. Therapeutically targeting this axis has become an area of intense research interest both for activating it against cancers/infections using agonists/adjuvants—and inhibiting it with antagonists/inhibitors to treat inflammatory/autoimmune disorders. Several small-molecule modulators are under investigation; however safety concerns remain due to its dual role in both protective immunity and pathological inflammation.

Other names

cGAS–STING pathwaycGAS/STING signaling cascadeCyclic GMP-AMP synthase–STING axis

Activation by small molecules or cyclic dinucleotides leads to increased type I interferon and inflammatory cytokine production, enhancing antitumor or antiviral immunity. Inhibition reduces inappropriate inflammation in autoimmune or degenerative diseases.