The cGAS–STING pathway in cancer immunotherapy: prognostic value and therapeutic potential
9 affiliations
- 1Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center
- 2Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah
- 3Department of Immunology, Roswell Park Comprehensive Cancer Center
- 4Department of Pharmacology and Toxicology, College of Osteopathic Medicine, Michigan State University
- 5Biodesign Institute, Arizona State University
- 6Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera
- 7University of Texas Southwestern Medical Center
- 8Department of Biochemistry and Chemistry, University of Toledo
- 9Department of Chemistry, New Mexico Highlands University
Abstract
Despite major advances in T cell-directed cancer immunotherapy, many patients fail to achieve durable responses, underscoring the need for approaches that mobilize additional arms of the immune system. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as a central cytosolic DNA sensor that initiates robust type I interferon signaling and bridges innate and adaptive antitumor immunity. Clinically, heightened cGAS-STING activity correlates with improved survival and enhanced responsiveness to immune checkpoint blockade in subset of tumor types. Preclinical studies have further demonstrated that the pharmacologic or genetic activation of cGAS-STING suppresses tumor growth, promotes dendritic cell maturation, increases effector immune infiltration, and synergizes with PD-1/PD-L1 inhibition. However, the spectrum of tumors that derive the greatest therapeutic benefit from STING activation and the mechanisms underlying pathway silencing or non-responsiveness remain incompletely defined. In this review, we integrate mechanistic, preclinical, and clinical evidence across solid tumors and hematologic malignancies to delineate the roles of cGAS-STING as both a prognostic biomarker and a therapeutic target. Our synthesis highlights the context-dependent nature of cGAS-STING signaling, with therapeutic outcomes shaped by STING pathway integrity, tumor mutational burden, cytosolic DNA load, and the immunologic composition of the tumor microenvironment. Importantly, we examine emerging evidence that excessive, systemic, or chronic STING activation can drive immune exhaustion, tolerogenic myeloid reprogramming, and treatment-limiting toxicity, which are factors likely to contribute to efficacy limitations of the first-generation STING agonists. We further discuss how rational combination strategies, optimized delivery platforms, and the kinetic control of STING activation may overcome these barriers. Collectively, this synthesis provides a conceptual framework to guide the development of next-generation immunotherapies that leverage cGAS-STING signaling while avoiding the immunosuppressive consequences of dysregulated innate immune activation.
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BibTeX
@article{alabi2026cgassting,
title = {{The cGAS–STING pathway in cancer immunotherapy: prognostic value and therapeutic potential}},
author = {Faizah A. Alabi and Sikiru Opeyemi Imodoye and Kamoru Ademola Adedokun and Mohamed Ashraf Eltokhy and Marina Curcic and Ebenezer Okoyeocha and Ishor Thapa and Sunil Tiwari and Ayorinde Víctor Ogundele and Tolulope E. Ayo and Omoniyi B. Awe and Muh'd Saheed Kolawole Abd-Rouf},
journal = {Frontiers in Immunology},
year = {2026},
month = jun,
doi = {10.3389/fimmu.2026.1760947},
url = {https://doi.org/10.3389/fimmu.2026.1760947},
note = {CC BY},
}
RIS
TY - JOUR
TI - The cGAS–STING pathway in cancer immunotherapy: prognostic value and therapeutic potential
AU - Faizah A. Alabi
AU - Sikiru Opeyemi Imodoye
AU - Kamoru Ademola Adedokun
AU - Mohamed Ashraf Eltokhy
AU - Marina Curcic
AU - Ebenezer Okoyeocha
AU - Ishor Thapa
AU - Sunil Tiwari
AU - Ayorinde Víctor Ogundele
AU - Tolulope E. Ayo
AU - Omoniyi B. Awe
AU - Muh'd Saheed Kolawole Abd-Rouf
PY - 2026
DA - 2026/06/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1760947
UR - https://doi.org/10.3389/fimmu.2026.1760947
AB - Despite major advances in T cell-directed cancer immunotherapy, many patients fail to achieve durable responses, underscoring the need for approaches that mobilize additional arms of the immune system. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as a central cytosolic DNA sensor that initiates robust type I interferon signaling and bridges innate and adaptive antitumor immunity. Clinically, heightened cGAS-STING activity correlates with improved survival and enhanced responsiveness to immune checkpoint blockade in subset of tumor types. Preclinical studies have further demonstrated that the pharmacologic or genetic activation of cGAS-STING suppresses tumor growth, promotes dendritic cell maturation, increases effector immune infiltration, and synergizes with PD-1/PD-L1 inhibition. However, the spectrum of tumors that derive the greatest therapeutic benefit from STING activation and the mechanisms underlying pathway silencing or non-responsiveness remain incompletely defined. In this review, we integrate mechanistic, preclinical, and clinical evidence across solid tumors and hematologic malignancies to delineate the roles of cGAS-STING as both a prognostic biomarker and a therapeutic target. Our synthesis highlights the context-dependent nature of cGAS-STING signaling, with therapeutic outcomes shaped by STING pathway integrity, tumor mutational burden, cytosolic DNA load, and the immunologic composition of the tumor microenvironment. Importantly, we examine emerging evidence that excessive, systemic, or chronic STING activation can drive immune exhaustion, tolerogenic myeloid reprogramming, and treatment-limiting toxicity, which are factors likely to contribute to efficacy limitations of the first-generation STING agonists. We further discuss how rational combination strategies, optimized delivery platforms, and the kinetic control of STING activation may overcome these barriers. Collectively, this synthesis provides a conceptual framework to guide the development of next-generation immunotherapies that leverage cGAS-STING signaling while avoiding the immunosuppressive consequences of dysregulated innate immune activation.
SN - 1664-3224
ER -