Cyclic GMP-AMP synthase-Stimulator of interferon genes-Transcription factor p65 signaling pathway (cGAS-STING-p65 pathway)

The cGAS-STING-p65 signaling pathway is a fundamental innate immune sensing mechanism that detects cytosolic double-stranded DNA (dsDNA) from pathogens or damaged host cells [1.1.1, 1.2.1]. Upon DNA binding, the enzyme cyclic GMP-AMP synthase (cGAS) produces the second messenger 2'3'-cGAMP, which activates the adaptor protein stimulator of interferon genes (STING) [1.1.4, 1.1.5]. Activated STING translocates to the Golgi apparatus and recruits kinases such as TBK1 and IKK to activate the transcription factors IRF3 and NF-kappaB (specifically the p65 subunit) [1.2.1, 1.2.5]. This activation leads to the production of Type I interferons and pro-inflammatory cytokines, which are essential for antiviral defense and antitumor immunity [1.1.1, 1.3.1]. However, chronic or aberrant activation of this pathway is linked to various inflammatory and autoimmune disorders, including Aicardi-Goutieres syndrome and systemic lupus erythematosus [1.1.2, 1.1.4]. In the context of cancer, the pathway can promote an immunosuppressive environment if chronically activated, but acute activation is a potent driver of T-cell recruitment [1.3.1]. Consequently, the pathway is a major focus for drug development, with STING agonists being explored for cancer immunotherapy and cGAS or STING inhibitors for treating chronic inflammatory conditions [1.2.4, 1.3.1]. Therapeutic challenges include managing the risk of cytokine release syndrome and ensuring precise modulation to avoid systemic toxicity [1.3.1].

Other names

cGAS-STING-NF-kappaB pathwaycGAS-STING-RelA pathwayDNA-sensing pathwaycGAS-STING-p65 axis

Activation of STING to induce type I interferons for oncology, or inhibition of cGAS/STING to suppress pathological inflammation in autoimmune diseases.