MINI REVIEW article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1631132
STING-targeting PROTACs: Emerging therapeutic tools for enhanced immunotherapy in inflammatory diseases
Provisionally accepted
- 1Qingdao Traditional Chinese Medicine Hospital, Qingdao Hiser Hospital Affiliated of Qingdao University, Qingdao, China
- 2Department of intervention, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
- 3Qingdao University, Qingdao, China
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The stimulator of interferon genes (STING) pathway is a central regulator of innate immunity, mediating host defense against pathogens but driving chronic inflammation when dysregulated-underpinning autoimmune diseases, fibrosis, and cancer.Traditional therapies targeting STING (e.g., small-molecule inhibitors, monoclonal antibodies) face limitations including incomplete pathway suppression, off-target effects, and reliance on continuous dosing. Proteolysis-targeting chimeras (PROTACs) offer a transformative approach by enabling selective degradation of STING, achieving sustained suppression of pathological signaling. However, critical gaps remain in understanding their selectivity for pathological vs. homeostatic STING activity, risks of immune suppression, and translational challenges. This review critically evaluates the rationale for STING degradation, with a comparative analysis of recent PROTAC designs (including warhead, E3 ligase, and linker optimization) and their pharmacokinetic/pharmacodynamic trade-offs. We address compensatory innate immune pathways, biomarker development hurdles, and safety risks, highlighting strategies to enhance specificity and clinical utility. STING-targeting PROTACs hold promise for inflammatory diseases, but their success depends on overcoming these challenges.
Keywords: STING, PROTACs, Immunotherapy, Protein degradation, Inflammatory diseases
Received: 28 May 2025; Accepted: 26 Aug 2025.
Copyright: © 2025 Jiang, Yang, Liu, Niu and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wanpeng Yu, Qingdao University, Qingdao, China
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