Cyclic GMP-AMP synthase–Stimulator of interferon genes–Nuclear factor kappa-light-chain-enhancer of activated B cells signaling axis (cGAS–STING–NF-κB axis) (cGAS–STING–NF-κB axis)

The cGAS–STING–NF-κB signaling axis is a fundamental innate immune pathway in macrophages that detects double-stranded DNA (dsDNA) in the cytoplasm, which serves as a marker for infection or cellular damage (Nature Reviews Immunology, 2019, PMID: 30770883). The enzyme cyclic GMP-AMP synthase (cGAS) acts as the primary sensor, binding to dsDNA and catalyzing the synthesis of the second messenger cyclic GMP-AMP (cGAMP) (Science, 2013, PMID: 23258413). cGAMP then binds to the stimulator of interferon genes (STING) on the endoplasmic reticulum, triggering a conformational change that allows STING to recruit and activate the IκB kinase (IKK) complex (Cell, 2013, PMID: 23722159). This activation leads to the phosphorylation and degradation of IκB, permitting the transcription factor NF-κB to translocate into the nucleus and initiate the expression of pro-inflammatory cytokines and type I interferons (Nature Communications, 2017, PMID: 28931823). While this axis is vital for defense against pathogens, its chronic activation is a driver of autoimmune diseases such as Aicardi-Goutières syndrome and systemic lupus erythematosus, making it a target for inhibitory drugs (Nature, 2014, PMID: 24948750). Conversely, STING agonists are being developed as cancer immunotherapies to turn “cold” tumors “hot” by stimulating macrophage-mediated inflammatory responses within the tumor microenvironment (Journal of Hematology & Oncology, 2020, PMID: 32819424).

Other names

cGAS-STING pathwayDNA-sensing inflammatory axiscGAS-STING-IKK-NF-κB signaling cascadeCytosolic DNA-sensing pathway

Activation of cGAS by cytosolic DNA leads to the production of cGAMP, which binds and activates STING; activated STING then recruits the IKK complex to trigger NF-κB nuclear translocation and the subsequent transcription of pro-inflammatory genes.