Aug 2026· Experimental Hematology· Vol 162, pp.
105490
· 0 citations· 82 references
Medicine
TL;DR
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.
Abstract
The 'cyclic GMP-AMP synthase-Stimulator of interferon genes' (cGAS-STING) pathway is a key component of the innate immune machinery, that detects the presence of cytosolic dsDNA and initiates type I interferon-driven inflammation, resulting in downstream immune responses. In cancer, aberrant activation or suppression of this signaling pathway connects genomic instability with immune surveillance, causing context-dependent outcomes that can either augment antitumor immunity or promote tumor progression. This paradox can be exemplified using acute myeloid leukemia (AML), a genetically and clinically heterogeneous hematologic malignancy with poor long-term survival, as a model disease. Emerging evidence indicates that cGAS-STING signaling plays multifaceted roles in AML pathogenesis, influencing leukemic cell survival, stemness, inflammatory signaling, and interactions with the immune microenvironment. Genetic and epigenetic alterations common in AML engage the cGAS-STING axis to drive chronic inflammatory states, clonal expansion, and leukemic transformation, while acute or therapeutic activation of STING can improve anti-leukemic immunity. Pharmacologic STING activation promotes dendritic cell maturation, type I interferon production, and cytotoxic T cell and NK cell responses, and can synergize with hypomethylating agents, PARP inhibitors, immune checkpoint blockade, and nanoparticle-based delivery systems. This review highlights current understanding of cGAS-STING biology, its contentious roles in cancer, and its specific functions in AML, highlighting therapeutic opportunities, caveats and challenges. We discuss 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, positioning cGAS-STING as a promising therapeutic target and biomarker of sterile inflammation in AML. Teaser Abstract: In this review article, we have discussed 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, positioning cGAS-STING as a promising therapeutic target and biomarker of sterile inflammation in acute myeloid leukemia.
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
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
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.
Xin-Ru Zhao, Shuai Meng, Hanzeng Cheng et al.· Cancer Biology and Medicine· 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
Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy in which inflammatory signaling plays a pivotal role in disease pathogenesis. The dysregulation of the cytokine network leads to an increased abundance of pro-inflammatory mediators, such as IL-1β, TNF-α and IL-6, relative to anti-inflammatory cytokines like TGF-β and CXCL12. This disbalance in cytokine levels is closely associated with tumor development and fosters a pro-tumorigenic microenvironment by facilitating leukemic cell proliferation, reducing survival rates, and promoting drug resistance. In addition, inflammatory cytokines have been shown to preferentially support hematopoietic stem and progenitor cell populations harboring mutations associated with clonal hematopoiesis. This review summarizes the current knowledge on inflammatory cytokines and signaling pathways in AML, focusing on: (i) their mechanisms of action and implications for immune tolerance and clonal hematopoiesis and (ii) the emerging therapeutic strategies targeting these pathways to improve clinical outcomes for patients with AML.
Toon Suls, E. Lion, Florian Van Oers et al.· Cytokine & growth factor rev...· 0 citations
Evidence linking dysregulated cGAS–STING activation to inflammatory remodeling, senescence-associated changes, cell injury, fibrosis, and tissue dysfunction is synthesized, while highlighting the context-dependent roles of this pathway across physiological aging and ARDs.
Yingying Xu, Weidong Wu, Yifan Guo et al.· Archives of pharmacal resear...· 0 citations
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