Therapeutic targeting of the cGAS-STING pathway in human disease
Akanksha S. Mahajan, Connor M. Forsyth, Cao Dai Phung, Xinhe Shen, Rachel Jarvis, Alexander H. Stegh
Akanksha S. Mahajan, Connor M. Forsyth, Cao Dai Phung, Xinhe Shen, Rachel Jarvis, Alexander H. Stegh
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Review Series

Therapeutic targeting of the cGAS-STING pathway in human disease

Abstract

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed as a uniformly beneficial antiviral and antitumor signaling axis, emerging evidence reveals that cGAS-STING functions as a context-dependent immune rheostat whose impact is dictated by signal magnitude, timing, cellular origin, subcellular localization of signaling components, and tissue context. These parameters explain why pathway activation can promote tumor rejection, vaccine efficacy, and host defense in some settings yet drive immune suppression, metastasis, neuroinflammation, or autoinflammatory disease in others. In this Review, we synthesize mechanistic and clinical insights across agonist and antagonist strategies targeting the cGAS-STING pathway in cancer, infectious disease, neurodegeneration, and interferonopathies. We highlight why first-generation STING agonists have underperformed clinically and how next-generation delivery systems and cGAS-directed approaches may overcome these limitations. We propose a disease-centric framework that integrates spatial delivery, dosing architecture, and pharmacodynamic biomarker discovery to enable rational modulation of cGAS-STING, repositioning the pathway as a tunable immunologic control node for precision therapy rather than a binary on/off switch.

Authors

Akanksha S. Mahajan, Connor M. Forsyth, Cao Dai Phung, Xinhe Shen, Rachel Jarvis, Alexander H. Stegh

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Figure 4

The biological consequences of cGAS-STING activation are shaped by signal magnitude, duration, cellular context, subcellular localization, and route of delivery.

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The biological consequences of cGAS-STING activation are shaped by signa...
(A) Temporal kinetics and signal amplitude determine whether pathway activation promotes immune tolerance, protective immunity, or excessive inflammatory injury. Low-level or poorly sustained signaling may favor tolerance and Treg programs, whereas appropriately timed intermediate signaling supports DC activation, antigen presentation, and productive T cell immunity. In contrast, excessive or prolonged activation can drive ablative inflammation, cytokine release, and tissue damage. (B) Cellular identity critically influences the outcome of STING activation. In DCs, cGAS-STING signaling promotes antigen presentation and T cell priming; in tumor cells, aberrant pathway activation can contribute to immune evasion or tumor-promoting inflammation; in myeloid and stromal compartments, it regulates inflammatory remodeling, tissue repair, and extracellular matrix programs; in endothelial cells, it can impair vasodilation, increase leukocyte adhesion, and promote vascular permeability. (C) Subcellular localization further constrains pathway output. Cytosolic DNA activates cGAS and downstream STING signaling, whereas nuclear cGAS is functionally restrained to preserve genome integrity and prevent aberrant inflammatory activation. (D) Route of administration and spatial compartmentalization provide additional opportunities to tune pathway output. Intratumoral delivery can concentrate innate immune activation within the TME; intranasal delivery may engage CNS-associated mucosal, lymphatic, and perivascular routes; vaccination strategies can target draining lymph nodes and antigen-presenting cells; and systemic delivery may broaden tissue exposure but increase the risk of inflammatory toxicity or immune suppression. (E) Dosing architecture defines the therapeutic window of cGAS-STING modulation. Therapeutic outcomes are determined by the integrated calibration of dose, schedule, duration, and exposure window, which together define the magnitude and temporal profile of pathway engagement. Optimized, often intermittent or tissue-targeted dosing is required to achieve efficacy while preserving homeostatic immune function. Together, these parameters define the therapeutic window for cGAS-STING agonists and antagonists and highlight the importance of context-specific dosing, delivery, and pharmacodynamic monitoring.