Therapeutic targeting of the cGAS-STING pathway in human disease
- 1Taylor Family Department of Neurosurgery, The Brain Tumor Center, Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri, USA
- 2Interdisciplinary Biological Sciences Graduate Program, International Institute for Nanotechnology, Northwestern University, Evanston, Illinois, USA
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.
Related
- Targeting the TL1A pathway in inflammatory bowel disease: mechanistic insights and emerging therapeutic pipeline
- The cGAS-STING pathway in traumatic brain injury: mechanisms of neuroinflammation and therapeutic strategies
- STING/Type I Interferon Pathway Activation Confers Multimodal Therapeutic Benefits in Osteomyelitis
- cGAS-STING pathway in digestive tract cancer: From molecular mechanisms to therapeutic applications (Review)
- The cGAS–STING pathway in tumor immunity: dual roles, regulatory mechanisms, and precision therapeutic strategies
BibTeX
@article{mahajan2026therapeutic,
title = {{Therapeutic targeting of the cGAS-STING pathway in human disease}},
author = {Akanksha S. Mahajan and Connor M. Forsyth and Cao Dai Phung and Xinhe Shen and Rachel Jarvis and Alexander H. Stegh},
journal = {Journal of Clinical Investigation},
year = {2026},
month = jun,
doi = {10.1172/jci204547},
url = {https://doi.org/10.1172/jci204547},
note = {CC BY},
}
RIS
TY - JOUR
TI - Therapeutic targeting of the cGAS-STING pathway in human disease
AU - Akanksha S. Mahajan
AU - Connor M. Forsyth
AU - Cao Dai Phung
AU - Xinhe Shen
AU - Rachel Jarvis
AU - Alexander H. Stegh
PY - 2026
DA - 2026/06/30
JO - Journal of Clinical Investigation
DO - 10.1172/jci204547
UR - https://doi.org/10.1172/jci204547
AB - 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.
SN - 0021-9738
SN - 1558-8238
ER -