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STING pathway as a cancer immunotherapy: Progress and challenges in activating anti-tumor immunity

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Abstract

The stimulator of the interferon genes (STING) signaling pathway plays a crucial role in innate immunity by detecting cytoplasmic DNA and initiating antiviral host defense mechanisms. The STING cascade is triggered when the enzyme cyclic GMP-AMP synthase (cGAS) binds cytosolic DNA and synthesizes the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum adaptor STING, leading to the activation of kinases TBK1 and IRF3 that induce interferon production. Secreted interferons establish an antiviral state in infected and adjacent cells. Beyond infections, aberrant DNA in cancer cells can also activate the STING pathway. Preclinical studies have shown that pharmacological STING agonists like cyclic dinucleotides elicit antitumor immunity when administered intratumorally by provoking innate and adaptive immunity. Combining STING agonists with immune checkpoint inhibitors may improve outcomes by overcoming tumor immunosuppression. First-generation STING agonists encountered challenges like poor pharmacokinetics, limited tumor specificity, and systemic toxicity. The development of the next-generation STING-targeted drugs to realize the full potential of engaging this pathway for cancer treatment can be a solution to overcome the current challenges, but further studies are required to determine optimal applications and combination regimens for the clinic. Notably, the controlled activation of STING is needed to preclude adverse effects. This review explores the mechanisms and effects of STING activation, its role in cancer immunotherapy, and current challenges.

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This study was written by the authors.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Fasa University of Medical Sciences, Fasa, Iran

    Mohammad Mahdi Mokhtari Tabar

  2. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Mahnaz Fathi

  3. Faculty of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

    Fatemeh Kazemi

  4. Department of Hematology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

    Ghazal Bazregari

  5. Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran

    Ghazal Bazregari & Abdolmajid Ghasemian

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A.G. conceptualized the study. M.M. collected the data and wrote the manuscript. M.F. F.K. and G.B. wrote the text and revised it. A.G. edited and approved the text. All authors reviewed the manuscript.

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Correspondence to Abdolmajid Ghasemian.

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Tabar, M.M.M., Fathi, M., Kazemi, F. et al. STING pathway as a cancer immunotherapy: Progress and challenges in activating anti-tumor immunity. Mol Biol Rep 51, 487 (2024). https://doi.org/10.1007/s11033-024-09418-4

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  • DOI: https://doi.org/10.1007/s11033-024-09418-4

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