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

The cGAS-STING signaling pathway is a fundamental component of the innate immune system responsible for detecting the presence of cytosolic double-stranded DNA, which typically indicates viral infection, cellular damage, or tumorigenesis. Upon binding to DNA, the enzyme cyclic GMP-AMP synthase (cGAS) catalyzes the production of the second messenger cyclic GMP-AMP (cGAMP), which subsequently binds to and activates the stimulator of interferon genes (STING) protein located on the endoplasmic reticulum. Activation of STING triggers a downstream signaling cascade involving TBK1 and IRF3, leading to the robust production of Type I interferons and pro-inflammatory cytokines that mobilize the adaptive immune response. In oncology, the pathway is a major target for agonists designed to convert 'cold' tumors into immunologically 'hot' tumors by promoting T-cell infiltration and enhancing the efficacy of immune checkpoint inhibitors. Conversely, pharmacological inhibition of the pathway is being explored to treat autoimmune and inflammatory conditions, such as systemic lupus erythematosus and Aicardi-Goutières syndrome, where chronic activation by self-DNA leads to pathological inflammation.

Other names

cGAS-STING axiscGAS-STING-IRF3 pathwaycGAS-cGAMP-STING pathwayDNA-sensing pathwayMB21D1-TMEM173 axis

The pathway is targeted through two distinct modalities: STING agonists are used in cancer immunotherapy to stimulate the production of Type I interferons and activate CD8+ T-cells within the tumor microenvironment; alternatively, cGAS or STING inhibitors are utilized in inflammatory diseases to block the aberrant sensing of self-DNA and prevent the chronic secretion of pro-inflammatory cytokines.