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 2

Licensing cGAS: chromatin gating, nuclear envelope integrity, and spatial control.

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Licensing cGAS: chromatin gating, nuclear envelope integrity, and spatia...
To enable proper response of the innate immune system, cGAS must be tightly regulated and only activated at specific moments. Inside the nucleus, cGAS is sequestered on chromatin in an inactive state. Under specific conditions, the Mre11-Rad50-Nbs1 complex releases chromatin-bound cGAS, allowing its translocation and sensing of cytosolic dsDNA. cGAS activation is enhanced upon binding to dsDNA and forming phase-separated condensates, which create an environment that promotes efficient and robust enzymatic activity. cGAS activity is also regulated by posttranslational modifications (PTMs), including ubiquitination, phosphorylation, and lactylation, which influence cGAS stability, localization, and activation. In micronuclei (MN), histone modifications regulate the recruitment and localization of cGAS to micronuclear dsDNA. BAF plays multiple roles in cGAS regulation. BAF modulates cGAS access to micronuclear dsDNA primarily by maintaining nuclear and micronuclear envelope integrity, thereby limiting exposure of self-dsDNA to the cytosol. In addition, BAF blocks TREX1 activity in micronuclei to prevent degradation of dsDNA. cGAS localization is further regulated through trafficking to distinct cellular compartments, including recruitment to the plasma membrane by MYO1F. cGAS preferentially binds and responds to dsDNA longer than 20 bp. Together, these mechanisms regulate cGAS activation and the subsequent induction of STING-dependent inflammatory signaling pathways.