A detailed understanding of the cGAS-STING axis has substantial value in providing theoretical guidance and supporting clinical translation in the development of next-generation combination immunotherapies, as well as broadening the patient population benefiting from clinical interventions.
Abstract
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central sensor of innate immunity that plays critical roles in recognizing cytosolic DNA and initiating antitumor immune responses. However, this pathway exhibits extensive spatiotemporal duality and context dependency in tumor regulation. In recent years, modulating this pathway to convert immunologically "cold" tumors into immunologically "hot," inflamed tumors has emerged as a cutting-edge strategy to reverse resistance to immune checkpoint inhibitors (ICIs). This review outlines the molecular mechanisms underlying the activation and regulation of the cGAS-STING pathway, with emphasis on its complex role in orchestrating the tumor immune phenotypic switch. A nuanced analysis of the pathway's duality distinguishes between acute immunostimulatory activation and chronic, pro-tumorigenic inflammation driven by chromosomal instability (CIN). Furthermore, current evidence regarding direct and indirect T-cell modulation, as well as pathway-mediated remodeling of the tumor microenvironment (TME) across diverse malignancies, is discussed in detail. Crucially, the current bottlenecks in clinical translation are described, including evaluation of the failure of first-generation agonists and the promise of next-generation delivery platforms such as antibody-drug conjugates (ADCs) and nanoparticle systems. Finally, a novel strategic framework is proposed involving mapping of specific STING-targeted modalities to distinct TME phenotypes, such as immune-desert, immune-excluded, and exhausted-inflamed states. A detailed understanding of the cGAS-STING axis has substantial value in providing theoretical guidance and supporting clinical translation in the development of next-generation combination immunotherapies, as well as broadening the patient population benefiting from clinical interventions.
Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis, profound spatial and cellular heterogeneity, and a highly immunosuppressive microenvironment. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing axis that activates innate immune responses, largely through the induction of type I interferons and inflammatory signaling. Increasing evidence indicates that the role of cGAS-STING signaling in GBM is highly context dependent. Acute activation, particularly in immune cells, may enhance antitumor immunity by promoting interferon-driven immune activation and facilitating tumor immune recognition. In contrast, chronic, dysregulated, or tumor-intrinsic activation may promote NF-κB-mediated inflammation, immune evasion, genomic instability-associated adaptation, and therapeutic resistance. In this review, we summarize the canonical biology of the cGAS-STING pathway, its regulatory and escape mechanisms, its distinctive features in the central nervous system, and its expression and functional relevance in GBM. We further discuss STING-targeted therapeutic strategies, including STING agonist monotherapy, drug delivery systems, and rational combination approaches, and synthesize current preclinical and clinical evidence supporting their application in GBM. Finally, we highlight major translational challenges, including blood-brain barrier penetration, cell-type-specific pathway activation, treatment-induced pathway remodeling, and biomarker selection, and propose a heterogeneity-informed framework for patient stratification and precision immunotherapy development in GBM.
Yu-Zhu Long, Tong-Cui Jiang, Yu Long et al.· Biomedicine & pharmacotherap...· 0 citations
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of antitumor immunity, capable of converting immunologically "cold" tumors into inflamed, immune-responsive states. Cyclic dinucleotide (CDN) agonists have clinically validated the impact of targeting this axis but are limited by poor pharmacokinetics, limited tumor penetration, and delivery challenges. Non-CDN based small-molecule modulators such as MSA-2 and amidobenzimidazole (ABZI) directly modulate cGAS-STING signaling. Beyond direct receptor agonism, coupling with metals offer platforms with complementary strategies to engage and amplify cGAS-STING signaling. Complexes incorporating platinum, ruthenium, iridium, rhodium, gold, copper, manganese, or zinc exploit redox activity, coordination versatility, and photophysical properties to induce nuclear or mitochondrial DNA stress, disrupt organelle homeostasis, and promote immunogenic cell death. By coupling STING activation to ferroptosis, pyroptosis, or cuproptosis, these complexes form the foundation of self-emerging design principles with elaborate mechanistic insights, and translational challenges shaping immune modulation for therapeutics.
How context determines the consequences of cGAS/STING activation in cancer is examined, emerging therapeutic strategies that modulate this pathway are reviewed, and how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation is discussed.
Yi Wang, J. Angulo-Lozano, Yue-Qi Wang et al.· Journal of Clinical Investig...· 0 citations
How the delicate balance between acute and chronic STING signaling in the setting of underlying genetic regulation and immune landscape can play critical role in determining clinical outcome is discussed.
Satyaki Bhowmik, Subhadeep Ghosh, A. Sengupta· Experimental Hematology· 0 citations
ABSTRACT The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling pathway, as a key DNA sensor, plays a significant role in the regulation of innate immune responses. This pathway can be activated by sensing abnormal DNA, and is of great significance for resisting the invasion of pathogenic microorganisms and maintaining tissue homeostasis. In addition, the cGAS‐STING pathway plays a dual role in cancer, and oncogenic viruses can cause cell carcinogenesis in the body through multiple mechanisms, thereby affecting human health. This manuscript reviews the vital role of cGAS‐STING in the immune process, as well as the fact that viruses causing human tumor lesions can activate cGAS‐STING, leading to virus inhibition and further preventing the occurrence and development of related cancers, and the paradoxically promoted progression of related cancers by viruses through cGAS‐STING. And summarize the agonists and inhibitors that act in different ways based on the activation mechanism of cGAS‐STING.
Li-Mei Guo, Li Li, Fang Wang et al.· Cell Biochemistry and Functi...· 0 citations
It is reported that Casein Kinase 1 alpha operates as a bimodal regulator of the cGAS-STING pathway, and selective degradation of CK1α using molecular-glue degraders suppressed aberrant cGAS-STING-driven inflammation signaling in a chromosomally unstable triple-negative breast cancer cell line.
Jane Jardine, Marine Tarrillon, G. André-Grégoire et al.· Cell Death and Differentiati...· 0 citations
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