Jul 2026· European Journal of Pharmacology· Vol 1031, pp.
179144
· 0 citations· 118 references
Medicine
TL;DR
The mechanistic basis, pharmacological rationale, and translational challenges of targeting the extracellular cGAMP-ENPP1 axis in cancer are summarized and a biomarker-guided framework incorporating cGAMP-generating capacity, ENPP1 expression and enzymatic activity, STING-response competence, and on-treatment pharmacodynamic conversion is proposed.
Abstract
The extracellular cyclic GMP-AMP (cGAMP)-ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) axis is an emerging pharmacological target that links tumor-intrinsic DNA stress to antitumor immunity. Tumor cells can generate cGAMP in response to chromosomal instability, micronuclear rupture, replication stress, and therapy-induced DNA damage. After export into the tumor microenvironment, extracellular cGAMP may be transferred to antigen-presenting cells and activate stimulator of interferon genes (STING)-dependent type I interferon and C-X-C motif chemokine ligand 10 (CXCL10) programs, thereby supporting dendritic-cell activation, immune priming, and cytotoxic T-cell recruitment. ENPP1 restricts this process by degrading extracellular cGAMP and by contributing to nucleotide catabolism associated with AMP- and adenosine-dependent immunosuppression. Accordingly, pharmacological ENPP1 inhibition differs from direct STING agonism by preserving endogenous tumor-derived cGAMP rather than imposing exogenous receptor activation. This Review summarizes the mechanistic basis, pharmacological rationale, and translational challenges of targeting the extracellular cGAMP-ENPP1 axis in cancer. We discuss ENPP1 inhibitors and cGAMP-stabilizing approaches, focusing on mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) relationships, target engagement, therapeutic window, and potential immunotoxicological constraints. We also propose a biomarker-guided framework incorporating cGAMP-generating capacity, ENPP1 expression and enzymatic activity, STING-response competence, and on-treatment pharmacodynamic conversion. Finally, we evaluate rational combinations with radiotherapy, chemotherapy, DNA damage response-targeted agents, immune checkpoint blockade, and immune-metabolic modulators. Clinical translation will require patient stratification, schedule-aware combination design, and robust pharmacodynamic validation in early-phase studies.
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.
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.
Haiyan Jiang, Zhanzhan Li, Xia Li et al.· Frontiers in Pharmacology· 1 citation
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.
Xinrui Zhao, Shuai Meng, Hanzeng Cheng et al.· Cancer Biology and Medicine· 0 citations
The cyclic GMP-AMP synthase-stimulator of interferon genes pathway is a central innate immune axis that connects cytosolic DNA sensing with type I interferon production, dendritic-cell activation, and downstream T-cell priming. These functions have positioned stimulator of interferon genes (STING) as an attractive therapeutic target in cancer, driving the development of cyclic dinucleotides, non-nucleotide small molecules, and formulation-enabled agonist platforms. Yet early clinical experience has revealed a recurring gap between measurable target engagement and durable antitumor benefit. Understanding this gap requires a pharmacological analysis that moves beyond pathway-level description and considers agonist chemistry, binding mode, intracellular trafficking, and exposure pattern together with the tumor-context determinants that control productive immune conversion. In this review, we summarize the structural, molecular, and biochemical basis of STING agonism, with emphasis on ligand recognition, species-selective determinants, trafficking requirements, and the pharmacological consequences of route of administration and formulation design. We then use a barrier-oriented perspective to examine four recurrent limitations on productive STING agonism in tumors: compartment mismatch, metabolic constraints, extracellular cyclic GMP-AMP (cGAMP) neutralization, and chronic output drift. These barriers help explain why pathway engagement may not consistently produce antigen-presenting cell (APC)-centered interferon output, T-cell priming, and durable antitumor immunity. We close by mapping therapeutic strategies to the barrier each strategy is most likely to overcome and by outlining biomarker-guided principles for designing STING activation that is therapeutically productive, rather than merely detectable.
It is suggested that QUR concurrently elicits molecular hallmarks of ICD and activates the cGAS‑STING pathway through mtDNA release in HCC cells, which provides a preliminary mechanistic basis for exploring QUR as an immunomodulatory agent for HCC.
Adenosine deaminase acting on RNA 1 (ADAR1) is a critical regulator of innate immune signaling and a pan-cancer therapeutic target. Through catalyzing adenosine-to-inosine (A-to-I) editing and editing-independent mechanisms, ADAR1 suppresses activation of dsRNA sensing pathways, including protein kinase R (PKR), melanoma differentiation-associated protein 5 (MDA5), and oligodenylate-synthetase (OAS) signaling, that are critical for maintaining cellular tolerance to endogenous RNAs. In a subset of tumors characterized by elevated interferon-stimulated gene (ISG) expression and dsRNA stress, this function creates a dependency on ADAR1 for survival, establishing a therapeutic vulnerability that can be exploited to induce viral mimicry in cancer cells and enhance anti-tumor immune responses. Here, we review the emerging landscape of ADAR1 modulators, organizing reported compounds into mechanistic classes including nucleoside analogs, catalytic inhibitors, Zα domain modulators, RNA substrate engagement inhibitors, indirect pathway regulators, and PROTACs. We evaluate molecules within these classes with a focus on their mechanisms of action and experimental validation. We further discuss the challenges associated with distinguishing direct inhibition of ADAR1 activity from broader effects on RNA metabolism and innate immune activation. Finally, we highlight the therapeutic potential of ADAR1 targeting defined cancer subsets and examine combination strategies that leverage ADAR1 inhibition for improved sensitivity to current cancer therapeutics. Overall, this review outlines key considerations for the development of selective therapies targeting ADAR1.
Carolyn N. Ashley, Emmanuel Broni, Chanyah M. Wood et al.· Pharmaceuticals· 0 citations
