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

The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is a central component of the innate immune system responsible for detecting cytosolic double-stranded DNA (dsDNA) (Nature, 2013). Upon sensing DNA from pathogens or damaged host cells, the enzyme cGAS (MB21D1) produces the second messenger 2'3'-cyclic GMP-AMP (cGAMP), which subsequently binds to and activates the STING protein (TMEM173) located on the endoplasmic reticulum (Science, 2013). This activation triggers a signaling cascade through TBK1 and IRF3, leading to the robust induction of Type I interferons and other pro-inflammatory cytokines (Cell, 2013). In the context of oncology, pharmacological activation of STING is pursued to enhance the immunogenicity of the tumor microenvironment and promote T-cell-mediated anti-tumor responses (Journal of Clinical Investigation, 2015). Conversely, aberrant activation of this pathway is linked to various autoimmune and autoinflammatory conditions, such as Aicardi-Goutières syndrome and STING-associated vasculopathy with onset in infancy (SAVI), making pathway inhibitors a focus for treating chronic inflammation (New England Journal of Medicine, 2014).

Other names

cGAS-STING axisMB21D1-TMEM173 pathwayDNA-sensing pathwaycGAS-STING pathway

Agonism of the STING protein to induce Type I interferon production and enhance anti-tumor immunity; Inhibition of cGAS enzyme activity or STING activation to suppress pathological inflammation in autoimmune disorders.