Molecular mechanisms regulating cGAS/STING activation in health and disease
Min-Guk Cho, Rachel Lee, Jaycee Johnson, Gaorav P. Gupta
Min-Guk Cho, Rachel Lee, Jaycee Johnson, Gaorav P. Gupta
View: Text | PDF
Review Series

Molecular mechanisms regulating cGAS/STING activation in health and disease

Abstract

The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriate or sustained activation of this pathway can drive chronic inflammation, autoimmunity, and disease-associated immune dysfunction, which can promote cancer growth. Effective immunity therefore depends on precise regulatory control that restrains cGAS/STING activity under homeostatic conditions while preserving the capacity for swift and robust responses to diverse danger signals. In this Review, we synthesize emerging principles that regulate cGAS/STING signaling across cellular contexts to control signal initiation, amplification, and termination. We discuss how disruption, persistence, or pathological rewiring of these regulatory processes contributes to immune imbalance across health and disease, promoting chronic inflammation, immunosuppression, and tissue pathology, with particular relevance to tumor progression and therapeutic resistance. Finally, we consider how restoring appropriate cGAS/STING regulation, rather than simply enhancing or inhibiting pathway activity, may reestablish immune homeostasis and improve therapeutic outcomes in cancer and other inflammatory diseases, framing the pathway as a dynamic regulatory circuit rather than a simple linear signaling cascade.

Authors

Min-Guk Cho, Rachel Lee, Jaycee Johnson, Gaorav P. Gupta

×

Figure 4

Multilevel rewiring mechanisms of the cGAS/STING pathway in pathological conditions.

Options: View larger image (or click on image) Download as PowerPoint
Multilevel rewiring mechanisms of the cGAS/STING pathway in pathological...
(A) Epigenetic and spatial regulation. In physiological states, cGAS and STING promoters are active, and specific histone modifications may facilitate cGAS recruitment to micronuclei or chromatin, thereby promoting immune activation. Conversely, cancer cells rewire this pathway via promoter hypermethylation (silencing expression) or altered histone marks that lead to cGAS exclusion and immune evasion. (B) Metabolic and enzymatic control of cytosolic DNA sensing. Under normal conditions, low TREX1 activity and intact MRE11 complexes facilitate the liberation and sensing of dsDNA by cGAS. In rewired states, the pathway is inhibited by the upregulation of lactate (which inhibits cGAS DNA sensing and activation through cGAS lactylation), overexpression of the exonuclease TREX1 (which degrades cytosolic dsDNA), or MRE11 deficiency (leading to cGAS sequestration). (C) Regulation of intercellular cGAMP transmission. Physiologically, 2′3′-cGAMP is exported via transporters such as ABCC1 and transferred to bystander immune cells through gap junctions or channels (VRACs, P2X7R) to trigger immune activation. In the rewired context, overexpression of ENPP1 degrades extracellular cGAMP, preventing immune cell activation. (D) Modulation of downstream signaling outcomes. While acute inflammation triggers primarily IRF3-dependent canonical immune-protective signaling, along with NF-κB activation, chronic STING activation–associated ER stress promotes tachyphylaxis. This rewires the pathway toward a noncanonical, prometastatic axis mediated by PERK-eIF2α-ATF4 signaling, associated with ATF4-dependent and NF-κB–related inflammatory programs rather than IRF3-centered signaling.