Sting agonist 2018. , 2020) were agonists of human STING.

Sting agonist 2018 STING agonists have shown potential in enhancing immune responses, particularly in tumors resistant Nov 21, 2024 · Critically, STING activation with a synthetic murine-only agonist DMXAA was unable to induce TBK1 or IRF3 phosphorylation in the STAT3-deficient RPMS cells (Fig. The agonists aim to activate STING, with cyclic dinucleotides (CDNs) being the most common, while the inhibitors aim to block the enzymatic activity or Oct 22, 2018 · "We are encouraged by these early findings with our STING agonist, most notably the observations of several robust anti-tumor responses in patients receiving MK-1454 in combination with KEYTRUDA. Targeting STING with covalent small-molecule inhibitors Simone M. We found that STING expression was epigenetically suppressed Jan 16, 2025 · In this study, we demonstrated that endothelial STING expression was critical for STING agonist–induced antitumor activity. Haag1,4, Muhammet F. May 31, 2023 · Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity, yet the selective delivery of STING agonists to tumors following systemic administration remains challenging. Jun 30, 2024 · The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Preclinical studies Jun 28, 2023 · In addition to the aforementioned STING agonists, there is a subset of drugs that could be used for cancer therapy by activating the cGAS-STING pathway. The cyclic GMP-AMP synthase-stimulator interferon gene (cGAS-STING) pathway is an emerging therapeutic target for the prophylaxis and therapy of a variety of diseases, ranging from cancer, infectious diseases, to autoimmune disorders. Nov 15, 2018 · However, STING is located inside the cell, while current commercially available STING agonists are formulated in a soluble form, which may not gain ready access to the intracellular STING. Jan 27, 2023 · Purpose of Review New therapies are needed to potentiate the effects of current immunotherapies and overcome resistance. Apr 2, 2018 · Citation: Skouboe MK, Knudsen A, Reinert LS, Boularan C, Lioux T, Perouzel E, et al. Hence, to investigate the local effects of STING activation in normal skin, we injected mice subcutaneously with diamidobenzimidazole STING Agonist-1 (diABZI). Dec 11, 2018 · Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas. , 2015; Sali et al. However, use of STING agonists (STINGa) as a STING (Stimulator of Interferon Genes) agonists have emerged as promising agents in the field of cancer immunotherapy, owing to their excellent capacity to activate the innate immune response and combat tumor-induced immunosuppression. While STING agonists are expected to be of value mostly for cancer therapy, STING antagonists have a chance to find their home in many diseases that have a strong innate immune component. Impact: The possibility for systemic delivery of diABZI compounds may expand the use of STING agonists in cancer. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. 31, 32 Moreover, nuclear and mitochondrial DNA damage will be induced by exogenous stimuli, such as chemotherapy or The Stimulator of Interferon Genes (STING) pathway is implicated in the innate immune response and is important in both oncogenesis and cancer treatment. find that lower doses of STING agonist are optimal for generating robust systemic tumor-specific T cell responses and durable anti-tumor immunity. In this review, we focus on recent trends in the development of STING modulators, including structures, mechanisms, and clinical application. Stimulator of interferon genes (STING) is an endoplasmic protein that induces the production of proinflammatory Nov 9, 2018 · Aduro Biotech has reported its first data for STING agonist ADU-S100, hoping to rebuild confidence in the mechanism after lackluster data from Merck last month. Intratumoral (IT) administration of MK-1454, a cyclic dinucleotide STING agonist, results in complete tumor regression and enhances the efficacy of anti-PD1 therapy in mouse syngeneic models. However, STING is commonly suppressed in melanoma through mechanisms that remain unclear. Herein, we develop a nano-STING Jun 1, 2024 · Agonists of the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, a critical mediator of innate immune response to foreign invaders with DNA, have gained significant interest in cancer immunotherapy. Jun 10, 2025 · An innate immune system is the first line of defense and prevents the host from infection and attacks the invading pathogens. STING-activating drugs Insight into the roles of STING in immunomodulation indicated the potential of STING agonists as cancer therapeutics to activate antitumor immune responses [22]. , 2020) were agonists of human STING. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells May 8, 2025 · The great therapeutic potential of pharmacologically manipulating the cGAS-STING pathway for cancer immunotherapy is reflected in the numerous ongoing clinical trials with different STING agonists, mainly for the treatment of solid tumors. Recent studies revealed that STING adaptor associates with various diseases, and several modulators targeting STING have been identified including three agonists that have entered clinical trials for treating cancer over the past 2 years. Recent Findings Preclinical data has shown that the addition of a STING agonist enhances the effect of current treatments such as Dec 11, 2018 · Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. , 2018; Guo et al. Trials to determine optimal drug combinations and novel delivery mechanisms are continuing in development. MSA-2 is an agonist of stimulator of interferon genes (STING). Oct 8, 2021 · The differentially expressed genes between high and low cGAS-STING clusters were enriched in immune-related biological pathways. , 2021). STING activation by STING agonists leads to phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) with the release of type I interferons and Dec 1, 2020 · In this review, we will summarize recent advances in the STING pathway, activation of the STING pathway, STING-related diseases, as well as the rationale and progress in the development of targeting STING inhibitors and agonists. Multiple STING agonists were developed for cancer therapy study with great results achieved in pre-clinical work. Jul 10, 2025 · The paper reports on two trials of intratumoural cyclic dinucleotide STING agonist therapy with Ulevostinag (MK1454) in patients with a variety of solid cancers and lymphoma. STING agonists have shown potential in enhancing immune responses, particularly in tumors resistant to traditional therapies. One of these is MK-1454 which binds directly to STING in the cytosol. Mechanistically, carvedilol promotes STING dimerization to enhance type I interferon responses. The correlation between cGAS-STING signaling pathway and the tumor immune microenvironment in Background: STING is a core signaling hub molecule in the innate immune system, involved in various diseases, including infectious diseases, autoimmune diseases, tumors, aging, organ fibrosis, and neurodegenerative diseases. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING Apr 14, 2025 · Harrington KJ, Brody J, Ingham M, Strauss J, Cemerski S, Wang M et al (2018) Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas. Concept: The diABZI compound can be administered systemically to induce tumor regression in mice with colorectal cancer. “the host STING pathway as a critical mechanism of innate immune-sensing of cancer, driving the production of type-I IFNs and promoting aggressive antitumor responses” First draft submitted: 1 August 2018; Accepted for publication: 25 October 2018; Published online: 10 December 2018 Keywords: cancer immunotherapy cyclic dinucleotides • STING Nov 25, 2018 · The complex of STING agonist and nanoparticles has been tested in antitumor therapy. Sep 7, 2018 · The immunotherapeutic property of STING agonists is more potent to clear lymphoma than its cytotoxic property. Feb 1, 2018 · STING agonists co-administrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Sep 18, 2018 · It is known that the NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and the radioresistance of tumor cells. Jun 1, 2025 · The cGAS-STING signaling pathway plays a pivotal role in innate immunity against cancer, but the clinical application of STING agonists were hampered by inflammatory responses due to off-target activation. , 2018), and HIV vaccines (Chattopadhyay and Hu, 2020) by promoting dendritic cell (DC) activation, increasing antibody production, and enhancing T-cell responses. Agonists of stimulator of interferon genes (STING), a receptor that triggers an immune response when stimulated by pathogen DNA, have recently attracted interest as cancer immunotherapies, with Apr 16, 2025 · Dang et al. May 30, 2021 · The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. Summary: STING agonists are a new class of agents that activate the host response immune response to improve tumor control. Despite … Feb 1, 2023 · Although modulating STING has shown promise as a potential treatment for cancers and inflammatory and autoimmune diseases in substantial pre-clinical studies, current preliminary clinical results of STING agonists have demonstrated limited anti-tumor efficacy. Recently, multiple clinical trials of STING agonists have been conducted in hematological malignancies and solid tumors. Non-Nucleotide STING Agonists MSA-2 enhances antitumor activity of anti-PD-1 immune checkpoint inhibitor in tumor models that are poorly responsive to PD-1 blockade MSA-2 and anti-PD-1 are synergistic in inhibiting tumor growth both innate and adaptive immune function contribute to STING agonist-driven tumor regression Jul 24, 2024 · About half of human PDACs lacked STING expression in the cancer stroma, suggesting that STING activation in PDAC CAFs exerts an antitumor effect, and STING agonists can be more effective in tumors Aug 4, 2025 · In cancer immunotherapy, the stimulator of interferon genes (STING) pathway regulation has become a promising new approach, offering potential solutions to overcome limitations of current treatments. 48 and 1. – (BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that new data from Merck’s broad oncology portfolio and Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Despite promising preclinical data, biological and physical challenges persist in translating the success of STING agonists into clinical trials. Recently, a synthetic small molecule STING receptor agonist, dimeric amidobenzimidazole (diABZI), with much higher cellular potency than CDNs was reported (Ramanjulu et al. The most prominent tool compound STING agonist broadly used pre-clinically was DMXAA, a vascular disrupting agent known to possess anti-tumor activity. Aug 21, 2020 · Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. The murine STING agonist DMXAA elicits tumour regression upon intratumoral and intraperitoneal delivery22, suggesting that systemic delivery of a STING agonist engages anti-tumour mechanism(s Dec 1, 2020 · The cGAS‒STING‒TBK1 axis is appreciated as the major signaling pathway in innate immune response, which is closely linked to multiple diseases. Feb 11, 2025 · STING agonists also show potential in influenza (Luo et al. Nov 21, 2018 · Background: STING is an endogenous sensor of cGAMP, which is synthesized by cGAS following detection of cytoplasmic DNA. Specifically, activation of the cytosolic DNA sensor STING in antigen-presenting cells (APCs) induces a type I interferon response and cytokine production that facilitates antitumor immune therapy. In syngeneic mouse tumor models, subcutaneous … Sep 1, 2023 · Recent progress has been made in STING research, including recently identified STING-mediated regulatory pathways, the development of a new STING modulator, and the new association of STING with disease. Intratumoral STING pathway activation is a promising therapeutic approach to treat cancer. We first establish the molecular framework of STING activation before cataloging current pharmacological agonists and their clinical applications. 72 μM, respectively) and induces secretion of IFN-β from THP-1 cells by 129% relative to induction by 2'3'-cGAMP (Item No. Combining STING agonists with inhibitors of negative regulators in the NF-κB pathway may enhance anti-tumor immunity while controlling inflammation (55). diABZI is a novel synthetic STING agonist with a higher bioavailability and better tissue penetration than natural agonists, making it an attractive candidate for clinical applications [8]. We report that the dose of STING agonist affects local activation and systemic expansion of tumor-specific CD8 + T cells in implanted flank mouse models. α-Mangostin and G10 bind to and stabilize the CTD region of STING in THP-1 cells and HEK293T (the human embryonic kidney cell line), respectively, and activate the STING-TBK1-IRF3 pathway. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I Conclusion: In conclusion, STING agonist therapy normalized peritoneal tumor blood vessels, enhanced anti-cancer immune response, and synergized with PD-1 immune checkpoint inhibitor therapy in peritoneal carcinomatosis of colon cancer. As a cytosolic “the host STING pathway as a critical mechanism of innate immune-sensing of cancer, driving the production of type-I IFNs and promoting aggressive antitumor responses” First draft submitted: 1 August 2018; Accepted for publication: 25 October 2018; Published online: 10 December 2018 Keywords: cancer immunotherapy cyclic dinucleotides • STING Nov 25, 2018 · The complex of STING agonist and nanoparticles has been tested in antitumor therapy. STING agonists enhance the efficacy of atezolizumab in BCa immunotherapy by activating the IFN-β signaling pathway. Tumour immune transcriptomic profiling revealed higher IFN response, antigen presentation and MHC II genes in tumours from STING agonist-treated mice compared to vehicle controls. Taken together, these preclinical findings provide robust grounds for testing STING agonists in cancer patients. Jul 4, 2018 · Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein, which is a central signalling Oct 20, 2018 · First Presentation of Early Data for Merck’s Investigational STING Agonist (MK-1454) in Patients with Advanced Solid Tumors or Lymphomas at ESMO 2018 Congress Mar 27, 2025 · Preclinical studies demonstrated that STING agonists can trigger the cancer immunity cycle and increase type I interferon secretion and T cell activation, which subsequently induces tumor regression. Similar to the classical STING agonist, 2'3'-cGAMP, diABZI induces activation of type-I interferons and pro-inflammatory cytokines in vitro and in vivo [1]. 12 Aug 4, 2025 · In cancer immunotherapy, the stimulator of interferon genes (STING) pathway regulation has become a promising new approach, offering potential solutions to overcome limitations of current treatments. The STING agonists currently being tested in trials are ADU-S100/MIW815 and MK-1454, but additional molecules are advancing toward clinical development. (2018) STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. SITC 2018 Abstracts Innate Anti-Tumor Immunity (NK cells, monocytes, macrophages, etc. The preliminary data were first presented at ESMO in 2018; so, it has been a long road to get it into print. Mar 14, 2023 · Daiichi Sankyo has started clinical testing of a STING agonist for cancer, a class that has been hit by safety issues and discontinued programmes. Therefore, the purpose of this investigation was to thoroughly review existing knowledge in this field and provide perspective into the clinical potential of STING agonists in AML. Anti-IFNAR1 reversed the STING agonist promotion on TBK1, IRF3 and STAT1 phosphorylation in 4T1 cells (P < 0. Small molecule STING-activating immunomodulators have been long studied for the treatment of diseases, including cancer. Potent non-nucleotide-based STING agonist diABZI (CAS# 2138299-34-8), also known as diABZI (compound 3) trihydrochloride, is a novel non-nucleotide-based ligand that potently activates STING. Here we report the first-in-human results for the STING agonist BI 1387446 alone (Arm A) and in combination with ezabenlimab (Arm B). Hou et al. In this work, we found that a combination of the STING agonist CDG SF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. demonstrate that the deficiency of non-canonical NF-κB, but not canonical NF-κB, promotes radiation-induced anti-tumor immunity by regulating the STING-mediated type I IFN expression. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription … Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA 1 . 01). In situ vaccination with STING agonist can be enhanced by agents that improve APC or T-cell function such as anti-GITR and anti-PD-1. Unlike DMXAA, flavonoids α-Mangostin (Zhang et al. While many STING agonists yield remarkable outcomes in mice, clinical trials have, unfortunately, yielded disappointing results thus far4. Preclinical studies Jan 12, 2021 · STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. Finally, STING and/or CGAS expression is silenced by epigenetic mechanisms in various cancer types including colorectal tumors, 140 further supporting the advantage obtained by developing neoplasms as a consequence of STING inactivation. This review summarizes the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their clinical use as a new immune stimulatory therapy. 19887) when used at a concentration of 30 μM. STING agonists administered intratumorally show potent anti-tumor efficacy in a range of preclinical models; several agonists are in clinical Oct 16, 2018 · Stimulation of STING should be transient, not chronic, and use of STING agonists is limited to intratumoral injections, similar to TLR9, in order to avoid potentially severe systemic effects. MSA-2 reduces tumor growth in an MC-38 syngeneic Jul 26, 2018 · Article Open access Published: 26 July 2018 Translational Therapeutics STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in Oct 8, 2018 · The xanthone derivate 5',6'-dimethylxanthenone-4-acetic acid (DMXAA, also known as ASA404 or vadimezan) is a potent agonist of murine STING (stimulator of interferon genes), but cannot activate human STING. To address this problem, two or more agonist molecules are often used together to synergistically enhance immune efficacy. For example, synthetic cyclic dinucleotides that mimic the STING ligand cGAMP are being explored as an approach to activate STING. Its activation has shown great potential in anti-tumor and anti-infective therapies, with STING agonists emerging as a promising approach in cancer immunotherapy in Jan 9, 2019 · In November 2018, development of the first intravenous STING agonist (made up of two linked amidobenzimidazole compounds) with strong antitumor activity in a colon cancer model was reported by Ramanjulu and colleagues (9). Sep 6, 2023 · Meanwhile, Merck & Co has discontinued an in-house Sting agonist, ulevostinag (MK-1454), whose first clinical data stunned the 2018 ESMO meeting with a 0% response rate as monotherapy. Several agonists and inhibitors of the cGAS-STING pathway have been developed and evaluated for the treatment of various diseases. The relative potencies of compounds 16g, 24b, and 24e were measured by a STING competition binding assay. Gisou van Oct 9, 2018 · First-Time Data for Merck’s Investigational STING Agonist (MK-1454) and Multiple Novel Pipeline Candidates to be Presented KENILWORTH, N. However, direct stimulation of innate immunity through STING agonists is being actively pursed both in vivo and in clinical trials. Stimulator of interferon genes (STING) plays a vital role in the innate immune system. Herein we report that α-mangostin, which bears the xanthone skeleton, is an agonist of human … Jan 9, 2019 · Major finding: A dimeric amidobenzimidazole (diABZI) STING agonist enhances adaptive immunity and antitumor activity. Apr 1, 2022 · STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Engagement of the STING pathway is involved in spontaneous and treatment-induced anti-cancer immunity. 2′3′-cGAMP, a natural agonist of STING, shows anticancer activity via stimulation of immune cells but it is susceptible to degradation in vivo by Mar 1, 2021 · Furthermore, STING activation was found to effectively repress the replication of a broad range of DNA and RNA viruses as reviewed in (Ahn and Barber, 2019). While largely deployed against cancer, applications of STING agonists for treating infections have emerged in the past years (Chattopadhyay and Hu, 2020; Gall et al. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was Targeting STING with covalent small-molecule inhibitors Simone M. , 2018) and G10 (Banerjee et al. Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. Feb 7, 2022 · The STING agonist was nontoxic to the lung, liver, brain cortex and kidney. Jun 28, 2018 · Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. Subsequently, this knowledge has enabled STINGINN develop new therapeutic approaches to overcome these obstacle and to make non-immunogenic tumor cells (cold) highly immunogenic (hot) using STING agonists [referred to as STAVs- STING activators] [Ahn et al. Dec 28, 2018 · Agonists of stimulator of interferon genes (STING), a receptor that triggers an immune response when stimulated by pathogen DNA, have recently attracted interest as cancer immunotherapies, with Jan 16, 2024 · Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Following membrane rupture and oxidative stress of tumor cells by cytotoxic nanoparticles, STING activation can enhance antitumor immunity by increasing expansion of tumor-infiltrating antigen-presenting cells and CD8+ T cells [11]. STING agonists are envisioned as a way of complementing the antitumor activity of the patient’s immune system and immune Aug 21, 2020 · Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Dec 1, 2023 · STING (Stimulator of Interferon Genes) agonists have emerged as promising agents in the field of cancer immunotherapy, owing to their excellent capacity to activate the innate immune response and combat tumor-induced immunosuppression. Our findings suggest the potential benefit of combining STING agonists and immune checkpoint inhibitors in OSCC patients. Novel STING agonist strategies and agents in development. ) Return to Category List Search word or phrase: New Search Jan 6, 2025 · Mechanisms of CDNs-Based STING Agonists Tumor cells are characterized by genomic instability, susceptibility to oxidative stress, and exuberant metabolism, 29, 30 which result in micronucleus formation and chromatin fragment leakage, leaving dsDNA naked in the cytoplasm. . Here, we found that Mn²⁺ was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING … Sep 1, 2023 · Recent progress has been made in STING research, including recently identified STING-mediated regulatory pathways, the development of a new STING modulator, and the new association of STING with disease. Recent advances have revealed intricate mechanisms of STING activation and regulation, leading to the development of novel small-molecule agonists with improved properties. 5c) along with downstream In Brief Intratumoral STING pathway activation is a promising therapeutic approach to treat cancer. Survival of mice treated with a combination of carboplatin, STING agonist and anti-PD-1 antibody was the longest. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants 2 . , 2015). While nanoparticle-mediated delivery has dominated STING agonist research, this review highlights the emerging paradigm of STING agonists especially for non-cyclic dinucleotides (non-CDNs) engineered through covalent conjugation strategies, with a special focus on these STING agonists in clinical trials. This review STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer Abdi Ghaffari1, Nichole Peterson2, Kasra Aug 20, 2020 · Checkpoint inhibitors that unleash the immune system so it can fight cancer have proven powerful in many tumor types. Oct 15, 2019 · 3. The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. | Merck's experimental STING agonist MK-1454 only showed modest efficacy in Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising Mar 10, 2018 · Concordantly, cGAS–STING agonists, including STING-binding molecules and cGAMP derivatives, have been developed and explored in the context of monotherapy, combination therapy, and vaccine adjuvanticity (see below). Activation of STING with a specific agonist, as a monotherapy or in combination with anti-PD1 therapy, may be a promising novel anticancer strategy. 1 identified an orally available non-nucleotide human stimulator of interferon genes (STING) agonist, MSA-2 (benzothiophene oxobutanoic acid), with Aug 2, 2022 · Non-nucleotide synthetic STING agonists that induce ‘open’ or ‘closed’ STING dimer conformations have recently been identified and were demonstrated to elicit robust antitumor effects following systemic administration in rodent models. Jul 4, 2018 · The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes (STING) protein may help to develop therapies for the treatment of autoinflammatory Jan 1, 2021 · The adaptor protein STING plays a major role in innate immune sensing of cytosolic nucleic acids, by triggering a robust interferon response. This review provides a comprehensive exploration of the strategies employed to develop effective formulations for STING agonists, with particular emphasis on Oct 1, 2025 · This review systematically examines current advancements in cGAS-STING pathway modulation, with particular emphasis on translational applications in tumor immunotherapy. Dec 31, 2022 · The efficacy of STING agonists as effective stimulators of the anti-tumor response in AML is being investigated in numerous clinical studies. We found that STING expression was epigenetically suppressed Jul 1, 2018 · Preclinical characterization of GSK532, a novel STING agonist with potent anti-tumor activity [abstract]. Download: Download high-res image (234KB STING agonists also show potential in influenza (Luo et al. The past several years, especially 2018, has seen increasingly rapid advances in this field. J. Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Jan 9, 2020 · In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). Gisou van In this study we evaluate the impact of a STING agonist, ADU-S100, a synthetic cyclic dinucleotide (CDN) agonist of STING, known to activate all human and mouse STINGs and induce the expression of cytokines and chemokines [18], in combination with radiation, on local tumor control and effector T-cell functionality using the modified Levrat Oct 8, 2021 · Background DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) and its downstream signaling effector stimulator of interferon genes (STING) present a novel role in anti-tumor immunity. Despite the undeniable potential, which DDS hold in improving STING agonists’ clinical efficacy, no STING-DDS have entered clinical trials which is suggested here to be the next step in determining the true clinical translatability of STING agonists. As a cytosolic Apr 13, 2024 · We systematically investigated the function and mechanism of cross-talk between STING agonist diABZI and adaptive immune systems. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. , 2019), BCG (Erik et al. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity … Dec 11, 2018 · IT STING agonist delivery alters the TME, promoting cellular activation, maturation, and cytokine secretion that results in the expansion of CD8+ T cells (Corrales and Gajewski, 2015, Ng et al. STING activation by STING agonists leads to phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) with the release of type I interferons and Feb 1, 2023 · Although modulating STING has shown promise as a potential treatment for cancers and inflammatory and autoimmune diseases in substantial pre-clinical studies, current preliminary clinical results of STING agonists have demonstrated limited anti-tumor efficacy. Jun 16, 2020 · Finally, STING and/or CGAS expression is silenced by epigenetic mechanisms in various cancer types including colorectal tumors, 140 further supporting the advantage obtained by developing neoplasms as a consequence of STING inactivation. In summary, our work uncovers a mechanism by which STING can be inhibited pharmacologically and demonstrates the potential of therapies that target STING for the treatment of autoinflammatory disease. Aug 1, 2022 · This study reveals a small-molecule agonist, compound 53, that facilitates the oligomerization and activation of human STING by binding a cryptic pocket in the STING transmembrane domain. While high doses of STING agonist are effective at clearing injected tumors, Sivick et al. The findings provide the basis for repurposing carvedilol in the therapy of STING-related diseases. Feb 26, 2018 · In this study, we aimed to explore the therapeutic potential of STING agonist in murine model of non-small cell lung cancer to overcome immunotherapy resistance. Here, we will review the development of STING-targeting nanoformulations in the battle against cancer and infectious diseases (Figure 1). Dec 1, 2018 · Request PDF | Design of amidobenzimidazole STING receptor agonists with systemic activity | Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate Jan 12, 2021 · In a recent study in Science, Pan et al. ) Return to Category List Search word or phrase: New Search In addition to the aforementioned STING agonists, there is a subset of drugs that could be used for cancer therapy by activating the cGAS-STING pathway. Background: The STING pathway has been implicated in antitumor immunity and response to immune checkpoint inhibitors. STING activation in endothelium promoted vessel normalization and CD8 + T cell infiltration — which required type I IFN (IFN-I) signaling— but not IFN-γ or CD4 + T cells. 1 It binds to wild-type and HAQ variant STING in a 3 H-cGAMP filtration binding assay (EC 50 s = 2. This scholarly review examines the diverse categories of STING agonists, encompassing CDN analogues, non-CDN chemotypes In addition to the highly differentiated physicochemical properties and increased STING binding affinity of ABZI-based agonists compared with CDNs, these agonists efficiently activate STING in an open conformation without the need for lid closure, which may also contribute to their improved potency (Ramanjulu et al. Nov 9, 2018 · Aduro Biotech Presents Preliminary Results from Ongoing Phase 1 Trials of STING agonist ADU-S100 (MIW815) in Patients with Advanced Solid Tumors or Lymphomas November 09, 2018 07:30 ET | Source Aug 15, 2023 · Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. The stimulator of interferon genes (STING) has emerged as a promising target for cancer immunotherapy. In a randomized phase II clinical trial, feasibility and safety of addition of DMXAA or ASA404 to standard therapy of paclitaxel and carboplatin was assessed in patients with previously Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC. Aug 21, 2020 · Discovery and molecular pharmacology of non-nucleotide STING agonists that induce “closed” STING conformation and antitumor immunity are described. Most importantly, mice treated with a combination of carboplatin, STING agonist and the immune checkpoint inhibiting anti-PD-1 antibody showed the longest survival compared to carboplatin + STING agonist treatment. , Cancer Cell, 2018]. A wide range of pre-clinical experiments, translational data, and ongoing clinical trials support the therapeutic use of STING agonists in patients. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I t … Mar 30, 2022 · Numerous classes of STING agonists are being evaluated for use, including novel cyclic dinucleotides, next-generation noncyclic dinucleotides, bacterial vectors, and ENPP1 inhibitors. The stimulator of interferon genes genes (STING) pathway is an innate immune activating cascade that may enhance current cancer immunotherapies. Gulen1,4, Luc reymond2, Antoine Gibelin2, Laurence Abrami1, Alexiane Decout1, Michael Heymann1, F. Jan 1, 2020 · The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-pathway triggers innate immune responses by recognizing cytosolic DNA. For instance, E7766 is a macrocyclic bridging STING agonist with high anti-tumour activity in a mouse model of liver metastases and is also considered a clinical candidate (Kim et al. To our knowledge, current efforts are focused on Oct 9, 2024 · Therapeutic activation of STING to boost immune responses may inadvertently overactivate NF-κB, leading to harmful inflammation (54). In The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. Recently, the combination of cGAS-STING agonists and immunotherapy achieved promising results in some tumor types. Aug 8, 2018 · Combination treatment with carboplatin and STING agonist showed synergistic effect and longer survival compared to monotherapy. discover carvedilol, a clinically approved β-adrenergic receptor antagonist, as a STING activator through high-throughput screening. In syngeneic mouse tumor models, subcutaneous … Apr 17, 2018 · Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. STING activation leads to interferon production and activation of inflammatory pathways that facilitate cytolytic T cell priming. , 2018). Aug 14, 2025 · Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Nov 7, 2018 · A small-molecule agonist for the cGAS–STING pathway has systemic activity in a mouse model of colon cancer. Initial results of the MK-1454 FIH study as monotherapy (Arm 1) or in combination with Jun 22, 2020 · Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. fgj cauzfw smank kyf pcsjxrqp gyfpbjx adqfm rofe najdtncp ehfy alptz exgq auwd hmzwww ckgjvkf