cGAS-STING Pathway

The cGAS-STING pathway is a cytosolic (and nuclear) DNA-sensing arm of innate immunity: the enzyme cGAS detects double-stranded DNA and synthesizes the second messenger 2′,3′-cGAMP, which activates the adaptor protein STING to trigger IRF3- and NF-κB-dependent transcription of type I interferon and inflammatory genes. Beyond direct viral DNA, cGAS is activated by a range of endogenous DNA sources — including leaked mitochondrial DNA, micronuclei, R-loops, and derepressed retroelements — making it a general sensor of genomic and organellar stress rather than a purely antiviral system. STING also drives non-canonical outputs beyond interferon signaling, including NF-κB activation, non-canonical autophagy, lysosomal biogenesis, and multiple cell-death programs. Depending on context, cGAS-STING engagement can be protective (antiviral defense, antitumor immunity) or pathogenic (autoimmune interferonopathies, chronic inflammation, tumor-promoting signaling in chromosomally unstable cancers), with the balance determined by the magnitude, duration, and cellular origin of pathway activation.