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
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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

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Figure 3

Spatiotemporal regulation and intercellular propagation of STING signaling.

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Spatiotemporal regulation and intercellular propagation of STING signali...
This schematic delineates the intracellular life cycle of STING signaling and its expansion into a paracrine communication network. (i) ER-to-Golgi activation axis. Upon binding to 2′3′-cGAMP, ER-localized STING dimers undergo conformational changes and oligomerization. This active complex exits the ER via COPII-coated vesicles, trafficking through the ER-Golgi intermediate compartment (ERGIC) to the Golgi apparatus. (ii) Signaling bifurcation at the Golgi. At the Golgi, STING undergoes palmitoylation, establishing a platform for divergent downstream outputs. The pathway bifurcates into the canonical TBK1/IRF3 axis (inducing type I IFN) and additional STING outputs, including NF-κB activation and LC3-associated autophagy-dependent clearance of cytosolic DNA. (iii) Signal resolution. To ensure transient immunity and restore homeostasis, the kinase ULK1 phosphorylates STING and attenuates IRF3-dependent signaling, while activated STING is subsequently routed to lysosomal degradation. Recent studies indicate that degradation of activated STING proceeds primarily via ESCRT-dependent lysosomal microautophagy rather than canonical macroautophagy. (iv) Intercellular cGAMP networking. Parallel to cell-intrinsic signaling, 2′3′-cGAMP functions as an immunotransmitter. Its extracellular availability is tightly governed by the balance between export pathways or channels (e.g., ABCC1, LRRC8-containing VRACs), hydrolytic degradation by ectonucleotidases (ENPP1, SMPDL3A), and uptake by bystander cells via specific transporters (e.g., SLC46A2, SLC19A1), thereby propagating paracrine innate immunity.