Stimulator of interferon genes-TANK-binding kinase 1-interferon regulatory factor 3 signaling axis (STING-TBK1-IRF3 axis)

The Stimulator of interferon genes-TANK-binding kinase 1-interferon regulatory factor 3 (STING-TBK1-IRF3) signaling axis is a primary pathway of the innate immune system responsible for sensing cytosolic double-stranded DNA [1, 2]. This axis is typically initiated by the enzyme cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP) upon binding to DNA species derived from pathogens or damaged mitochondria [5, 14]. cGAMP then binds to the adaptor protein STING at the endoplasmic reticulum, inducing its translocation to the Golgi apparatus where it recruits and activates the kinase TBK1 [1, 14]. Subsequently, TBK1 phosphorylates the transcription factor IRF3, leading to its dimerization and nuclear translocation where it drives the expression of type I interferons and other pro-inflammatory cytokines [1, 10]. In the context of disease, this axis plays a critical role in anti-tumor immunity by promoting the maturation of dendritic cells and the cross-priming of cytotoxic T-cells [5, 23]. Conversely, over-activation is linked to autoimmune disorders and chronic inflammatory conditions such as Aicardi-Goutières syndrome and systemic lupus erythematosus [2, 16]. Therapeutically, STING agonists are being developed to enhance cancer immunotherapy by converting immunologically 'cold' tumors to 'hot' ones, while STING and TBK1 inhibitors are investigated for treating auto-inflammation [4, 9, 20].

Other names

cGAS-STING-TBK1 signaling axisSTING-TBK1-IRF3 pathwaycGAS-STING-IRF3 pathwaySTING signaling pathwayCytosolic DNA sensing pathway

STING agonists activate the axis by mimicking cyclic dinucleotides or inducing conformational changes in STING, leading to TBK1 recruitment and IRF3-mediated type I interferon production for anti-tumor immunity. Conversely, inhibitors of STING, TBK1, or the upstream sensor cGAS block this axis to reduce pathological cytokine levels in autoimmune and chronic inflammatory diseases.