The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential

The cGAS–STING pathway in tumor immunity: dual roles, regulatory mechanisms, and precision therapeutic strategies

The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, the core DNA-sensing mechanism in innate immunity, plays a pivotal role in linking tumorigenesis and the immune response. This review systematically elucidates the molecular activation mechanisms of this pathway and its complex regulatory networks within tumors, with a particular focus on analyzing its dual functions—tumor immune surveillance versus tumor promotion—and the determining factors involved. Current research indicates that acute activation of the cGAS–STING pathway potently suppresses tumors by inducing type I interferon responses, thereby promoting dendritic cell (DC) maturation and cytotoxic T lymphocyte infiltration. However, its chronic, persistent activation can paradoxically accelerate tumor progression and immune evasion by remodeling the immunosuppressive tumor microenvironment (TME), inducing chronic inflammation, and enhancing the intrinsic malignant phenotypes of tumor cells. Tumor cells tightly regulate the activity of this pathway through multiple mechanisms, including epigenetic silencing, aberrant post-translational modifications, autophagy-dependent degradation, and tumor microenvironment remodeling. Based on these findings, this review comprehensively summarizes therapeutic strategies targeting the cGAS–STING pathway. These include the latest advancements in STING agonist development, optimization strategies for combination therapies, and innovative applications of nano-delivery systems. Furthermore, we delve into the critical challenges hindering current clinical translation, including pharmacokinetic limitations, mechanisms of tumor resistance, STING genetic polymorphisms, and safety concerns. Finally, we explore future research directions, encompassing precision modulation strategies, personalized therapeutic approaches, and novel delivery systems, aiming to provide a theoretical foundation and innovative insights for the next generation of cancer immunotherapies centered on the cGAS–STING pathway.

cGAS-STING signaling in acute myeloid leukemia: biology, pathophysiology and therapeutic implications.

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.

cGAS-STING pathway activation drives the cold-to-hot tumor transition and sensitizes immunotherapy.

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.

cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.

Targeting the DNA damage response to reshape the tumor immune microenvironment

The DNA damage response (DDR) maintains genome stability through coordinated DNA repair, replication-stress signaling, and cell-cycle control. In cancer, DDR dysregulation promotes genomic instability, clonal evolution, and treatment resistance, while simultaneously creating therapeutically exploitable vulnerabilities. DDR alterations also reshape the tumor immune microenvironment by influencing cytosolic nucleic-acid sensing, neoantigen generation, antigen presentation, inflammatory signaling, and immune checkpoint regulation. However, these effects are highly context dependent. Acute activation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway may promote antitumor immunity, whereas persistent genomic stress and chronic inflammatory signaling can facilitate immune suppression and tumor progression. Clinically, mismatch repair deficiency and high microsatellite instability are established biomarkers for immune checkpoint blockade (ICB), whereas the predictive value of other DDR alterations remains variable. This review summarizes the major DDR pathways, their roles in tumor evolution and immune remodeling, and the rationale and limitations of combining DDR-targeted therapies with immunotherapy. We further discuss biomarker refinement, resistance mechanisms, and future strategies for translating genomic stress into durable antitumor responses.

The kinase CK1α coordinates the initiation and termination of the cGAS-STING pathway.