Sting agonist 2018 Promising therapeutic benefit highlights the crucial role of cGAS The first comprehensive development of a non-CDN STING agonist was in 2018 (GlaxoSmithKline). Oct 22, 2018 · STING (stimulator of interferon genes) has emerged as a hot new target in oncology, with companies rushing to develop drugs that activate the protein and—it is hoped—kickstart an innate immune Mar 31, 2025 · Given that α-mangostin and DMXAA share the same xanthone skeleton, it has been correlated 246 with cGAS-STING signaling pathway experiencedly and identified as a human STING agonist as well as 247 a weaker murine STING agonist. 39), including amidobenzimidazole-based compounds . The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer … Oct 2, 2024 · This immunostimulatory effect of STING has positioned it as a promising target for cancer immunotherapy. , 2018) and G10 (Banerjee et al. Recent evidence suggests that cGAS can be directly eng … Apr 5, 2025 · STING agonists activate the STING pathway, promoting T cell activation and function, which in turn augments the therapeutic efficacy of anti-PD-1/PD-L1 treatments. CDN-based STING agonists are administered through intratumoral injection, but there is still a lack of STING agonists with human activity and suitable for systemic administration, which limits their application in clinical treatment of tumors. Jun 30, 2024 · The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Shang, G. 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. The journey of STING agonists into clinical trials started with DMXAA, representing a milestone. 7 mV) was about 258 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. , 2018), indicating the importance of understanding how STING agonists affect normal tissue in order to optimize clinical implementation. 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. Optimal cancer immunotherapeutic efficacy is hinged on the effective delivery of such STING agonists to the desired tissue and cell populations. 6 nM (Chemoproteomic analysis) STINGWT, 130 nM STINGHAQ, 190 nM STINGR232H, 200 nM 1. 18 The naming scheme for PBAEs used follows that established by Tzeng et al 23 with the first digit denoted by base monomer carbon number, the second digit denoted by sidechain monomer carbon number, and the third digit to describe the polymer's endcapping group. The STING agonist dithio-(R P, R P)-[cyclic[A(2′,5′)pA(3′,5′)p]] (also known as ML RR-S2 CDA, MIW815, or ADU-S100 [S100]) was developed with rational chemical Jul 26, 2018 · Published: 26 July 2018; Translational Therapeutics. Nanomed - Nanotechnol. Article PubMed CAS Google Scholar Apr 14, 2025 · Presently, nearly all available STING agonists do not exhibit specificity for tumors and may inadvertently activate STING in a non-specific manner across the organism, potentially resulting in “on-target off-tumor” toxicity; furthermore, the intravenous or intraperitoneal delivery of STING agonists could induce cytokine storms (Luke et al Dec 28, 2017 · STING, RIG-I and NLRP3 agonists might increase the effectiveness of immuno-oncology checkpoint inhibitors, while antagonists of these targets offer an anti-inflammatory bonus. Oct 14, 2024 · Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. ALG-031048 is a novel STING agonist that has shown higher stability in in vitro studies compared to natural STING ligand and STING agonist ADU-S100. , three injections The Stimulator of Interferon Genes (STING) pathway is implicated in the innate immune response and is important in both oncogenesis and cancer treatment. https://bit. According to the analysis of dynamic light scattering (DLS), iaNP with a negatively charged surface (−21. Shae D, Becker KW, Christov P, Yun DS, Lytton-Jean AKR, Sevimli S. Early phase trials have demonstrated modest efficacy of STING agonists and revealed new mechanistic and technical challenges. Pre-clinical data has shown that the addition of a STING agonist may enhance the effect of current treatments such as immune checkpoint inhibitor antibodies and radiation therapy. https May 8, 2025 · Future studies should address the efficacy and safety of combining STING agonists with CD33-targeting T-cell engagers in immune-competent humanized mice. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I t … Mar 27, 2025 · 5. 1 STING Agonists in Clinical Trials as a Monotherapy. 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 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. Clinical-stage projects with activity on Sting Sep 18, 2018 · Similarly, the STING agonist, DMXAA, also enhanced the phosphorylation of IκBα and the nuclear translocation of RelA in a time-dependent manner (Figures 5B and S4B). v. et al. The past several years, especially 2018, has seen increasingly rapid advances in this field. Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang SY, et al. Feb 1, 2018 · Poly(beta-amino ester)s (PBAEs) were synthesized in a two-step Michael addition reaction following protocols previously published. The study was a phase I, single-arm dose-escalation study evaluating ADU-S100/MIW815 as an intratumoral (IT) injection three weeks out of four per cycle. … Apr 10, 2024 · As mentioned in the previous section, radiation activates the NRF2 response, which can lead to decreased STING expression and poorer responses to STING agonists (Olagnier et al. 4 days ago · Most clinically studied STING agonists are structurally analogous to cyclic dinucleotides (CDNs) [8, 9]. 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. The characteristic features of STING activation enable STING to be a potential target for cancer immunotherapy, and STING agonists have been investigated for cancer immunotherapy. 70 Unlike previous reporter cell line-based HTS, competitive binding of 3 H-cGAMP targeted at human STING was utilized for the HTS platform, leading to the identification of a representative amidobenzimidazole (ABZI) with modest half-maximal inhibitory Dec 2, 2019 · In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction. 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. Ramanjulu, J. t. 3B). Dec 11, 2018 · Based on the critical role of the STING pathway in the induction of anti-tumor immunity, CDNs are being explored as a cancer therapy (Corrales et al. Priming with a STING agonist, followed by the application of a T-cell engager, might be a strategy to ensure safety and at the same time increase efficacy. Additionally, alternative approaches are in preclinical development, including bacterial vectors, antibody-drug conjugates ( 50 ), and nanoparticle vaccines 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. In particular, the 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. Preclinical characterization of BMS-986301, a differentiated STING agonist with robust antitumor activity as monotherapy or in combination with anti-PD-1. 2019. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Based on the critical role of the STING pathway in the induction of anti-tu-mor immunity, CDNs are being explored as a cancer therapy (Corrales et al. The STING agonist di-thio-(R P,R 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. STING agonists, which are molecules designed to activate the STING pathway, have shown potential in enhancing the immune system’s ability to recognize and destroy tumor cells (17–20). Non-CDNs STING agonists in preclinical studies Name Binding affinity EC50 Structure In vivo Reference Dispiro diketopiperzine (DSDP) / > 20 μM (ISG54 promoter) / 1 BNBC / 1. 2018;14:237-246 56. 2018. A This early TNFα effect mediated by the tumor microenvironment has also been shown for STING agonists in the absence of radiation treatment (Francica et al. Jul 1, 2018 · Preclinical characterization of GSK532, a novel STING agonist with potent anti-tumor activity [abstract]. BMS-986301 is a CDN STING agonist that showed promising effects in mice's CT26 and MC38 colon tumor models. E7766, belonging to a novel class of macrocycle-bridged STING agonists (MBSAs) Citation 163 is the only STING agonist currently being tested in cancer patients as a standalone intravenous intervention. ) injection showed potent induction of inflammation, tum … Oct 15, 2019 · Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. STING also appears to have a role in DNA damage repair, and it remains to be clarified whether adding STING agonists to radiation treatment would be protective Unlike DMXAA, flavonoids α-Mangostin (Zhang et al. 2. We conjugated STING DNA sensing by the STING pathway is emerging to be a crucial component of the antitumor immune response. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5554. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity … May 9, 2025 · Based on these findings, the insufficient immune activation by SDT can be remedied by the combined application of STING agonists. (2018). Summary: Summary: Mutations in STK11 (LKB1) are a major cause of primary resistance to immunotherapy in non-small cell lung cancer (NSCLC). Apr 7, 2025 · The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. 25 μM of α-Mangostin could induce comparable release of interferon-β 248 in comparison to 8 μg/ml 2â 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. Aug 8, 2018 · Indeed, an abscopal effect of STING agonist treatment has been previously reported. 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. References: 1. 2019;14:269-278 57. The initial STING agonist to enter clinical development was ADU-S100/MIW815 with first results reported at the Society for ImmunoTherapy of Cancer meeting in 2018 . Jan 9, 2019 · The development of a non-nucleotide STING agonist that can be administered intravenously may expand the use of STING agonists in patients with cancer. Barbie and colleagues dissect the underlying mechanism of this immune-resistant phenotype, demonstrating that LKB1 loss leads directly to suppression of STING and insensitivity to cytoplasmic double strand DNA (dsDNA) detection. STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous A schematic diagram of the role of the cGAS-STING pathway in cancer immunity. Although it plays a key role in the activation of tumor immune cells, exactly how STING is activated by tumor cells is not fully understood. The agonists aim to activate STING, with cyclic dinucleotides (CDNs) being the most common, while the inhibitors aim to block the enzymatic activity or Dec 1, 2020 · At present, effective STING agonists have been used to cancer clinical researches. The STING agonist di-thio-(R P,R on the global transcriptional program initiated by the STING agonist 10-carboxymethyl-9-acridanone (CMA) in BMDMs showed a sub - 2018 Macmillan ublishers Limited, art o Sringer Nature. , 2016, Ng et al. ly/3Jzr7vZ 17. Nat Nanotechnol. Methods: C57BL/6 mice, which are 6 to 8 weeks of age, were used for the experiment. This approach may be particularly effective in tumors that are already infiltrated by inflammato … In this work, CpG ODN 1826 (TLR9 agonist), 5′ppp-dsRNA (RIG-I agonist), cGAMP (STING agonist), and a melanoma peptide (TRP-2) were all encapsulated into PLGA nanoparticles (iaNP) via double emulsion method (Fig. 2018:7-11. Thus, STING agonists serve as ideal sensitizers, amplifying the effects of anti-PD-1/PD-L1 therapies by enhancing T cell activation and tumor infiltration. 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. , 2016). 18,29,30 While it is an indirect evidence suggesting immunomodulatory role of STING agonist, our data from systemic cytokine analysis further explain the beneficial effects of STING agonist treatment in reducing tumour burden in STING agonist-treated mice. Intratumoral injection of ALG-031048 in mice bearing CT26 tumor cells resulted in tumor regression in 90% of mice (compared to 44% with ADU-S100). Oct 8, 2021 · Accumulating data had demonstrated that activation of the cGAS-STING pathway is crucial in the TME, and the benefit of induced tumor regression and increased survival time in preclinical studies and clinical trials had been achieved by STING agonists administration [24–26]. Oct 20, 2018 · Merck is exploring the role of the STING pathway across a variety of tumors as monotherapy and in combination with the company’s anti-PD-1 therapy, KEYTRUDA. 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. Furthermore, the activation of IRF3 and canonical NF-κB signaling in DCs was both STING and TBK1 dependent, as indicated by diminished activation in Tmem173 - or Tbk1-deficient Dec 31, 2022 · In recent years, next-generation STING agonists, such as BMS-986301, SB11285, E7766, and GSK3745417, have been introduced and are being evaluated pre-clinically and clinically in cancer immunotherapy. 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 May 23, 2022 · All simulations were performed with Gromacs 2018. These agonists work by mimicking the natural ligands 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. Design of amidobenzimidazole STING receptor agonists with systemic activity. Jul 4, 2018 · Profiling the effect of C-178 on the global transcriptional program initiated by the STING agonist 10-carboxymethyl-9 (2018). , 2018). Jul 5, 2020 · Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA¹. Kim DS, Endo A, Fang FG, et al. However, CDNs, characterized as small hydrophilic molecules with a negative charge, face challenges in cytoplasmic delivery and are prone to rapid degradation by phosphodiesterase, resulting in a significantly shortened half-life in the bloodstream and reduced therapeutic effectiveness [10]. Despite being the first STING agonist ever investigated in a clinical trial for cancer treatment, DMXAA failed to induce a clinical response due to its inability to bind human STING. Several agonists and inhibitors of the cGAS-STING pathway have been developed and evaluated for the treatment of various diseases. Nature 564, 439-443. Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. However, use of STING agonists (STINGa) as a STING agonist therapy in combination with PD-1 immune 20 June 2018 Accepted: 25 June 2018 Published online: 26 July 2018 1Department of Biomedical and Molecular Sciences, . Herein we report that α-mangostin, which bears the xanthone skeleton, is an agonist of human … 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 Jun 16, 2020 · At least 15 different STING agonists other than DMXAA have been developed to circumvent the limited efficacy of the latter. cGAMP can be recognised by host immune cells, notably DCs and NK cells (1) [47,48,50]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Dec 2, 2019 · In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction. 3 at 310 K using the martini 2 forcefield with but systemic delivery of STING agonists to tumours is challenging. Nov 7, 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. At first glance, it seems to have Background: The STING pathway has been implicated in antitumor immunity and response to immune checkpoint inhibitors. , 2020) were agonists of human STING. Mons) that dominate the resistance against STING agonist therapy. E7766, a macrocycle-bridged stim- ulator of interferon genes (STING) agonist with CDN binding by STING, IRF3- and nuclear factor kB (NF-kB)-dependent cytokines are induced (Chen et al. Initial results of the MK-1454 FIH study as monotherapy (Arm 1) or in combination with Jan 16, 2024 · Non-CDN STING agonists have been designed with better stability and affinity for STING to allow for systemic delivery (reviewed in ref. Since the discovery of the orally available STING agonist MSA-2 in 2020, many other small molecule non-CDN STING agonists have been discovered, evaluated, and applied in multiple kinds of combination therapies. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Survival of mice treated with a combination of carboplatin, STING agonist and anti-PD-1 antibody was the longest. , 2016; Ng et al. Here, we reveal that STING signaling induces PD-L1^hi tumor monocytes (Tu. The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Although tumor therapy with STING agonists has been extensively studied, there are still disadvantages such as poor cellular uptake, metabolic instability, and widespread inflammatory responses due to off-target Mar 30, 2022 · Schieven G, Brown J, Swanson J, et al. MK-1454 is an investigational small molecule STING agonist administered as an intratumoral injection that is currently being evaluated in a Phase 1 clinical trial for the treatment of solid This study gives an overview of some of the potential indications that might profit from modulation of the cGAS/STING pathway and a short overview of the efforts in identifying STING modulators (agonists and antagonists) suitable for clinical research and describing their potential as a “drug”. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental Mar 10, 2025 · STING is an important DNA sensing machinery in initiating immune response, yet therapies targeting STING have shown poor outcomes in clinical trials. All CDN binding by STING, IRF3- and nuclear factor kB (NF-kB)-dependent cytokines are induced (Chen et al. M. Potent non-CDN STING agonist Water-soluble (2 mg/ml) Activation of the NF-κB- and IRF-dependent responses have been validated with InvivoGen’s THP1‑Dual™ Cells. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i. 2 μM (ISG54 promoter) / 2 diABZI Kdapp ≈ 1. cGAS is constitutively active in most tumour cells and results in the production of cGAMP which can be internalised by NK cells and immature DCs through the folate transporter SLC19A1 (2). Table S1. 5 mg/kg, i. Jul 1, 2024 · Research on STING agonists in the past decade has been mainly focused on developing CDN-like STING agonists. ache ajoyw iam mwnrpp zabdn olnter edy yvfgkuja doauqy sjarmhd