Innate immune DNA-sensing pathway (DNA-sensing pathway)

The innate immune DNA-sensing pathway is a fundamental biological mechanism used by cells to detect the presence of double-stranded DNA (dsDNA) in inappropriate cellular compartments, such as the cytoplasm, which typically indicates viral infection, bacterial invasion, or endogenous cellular damage [1, 2]. The most prominent component of this system is the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis, where cGAS acts as a cytosolic DNA sensor that produces the second messenger cGAMP upon activation [1]. This molecule then binds to STING, triggering a signaling cascade through TBK1 and IRF3 that results in the robust production of type I interferons and pro-inflammatory cytokines [2]. Beyond cGAS-STING, other sensors like Toll-like receptor 9 (TLR9) in endosomes and the AIM2 inflammasome also contribute to DNA-mediated immune activation [3, 4]. Dysregulation of these pathways is a hallmark of various autoimmune diseases, such as Aicardi-Goutières syndrome and systemic lupus erythematosus, where the body fails to distinguish self-DNA from foreign DNA [2, 5]. In oncology, pharmacological activation of the DNA-sensing pathway is being heavily investigated as a strategy to turn cold tumors hot by promoting dendritic cell maturation and T-cell recruitment [5, 6].

Other names

cGAS-STING pathwayCytosolic DNA-sensing pathwayTLR9 signaling pathwayAIM2 inflammasome pathwayIFI16-mediated DNA sensing

STING agonism to induce type I interferon for cancer immunotherapy; STING or cGAS inhibition to reduce pathological inflammation in autoimmune diseases; TLR9 antagonism to prevent DNA-induced immune activation.