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<p>The stimulator of interferon genes (STING) is a crucial pattern recognition receptor that activates innate immunity, particularly in response to pathogen infection and various stimuli. Notably, activation of STING exhibits remarkable potential in enhancing anti-tumor immunity, underscoring the significance of discovering STING small molecule agonists. Recently, zinc pyrithione (ZPT), a marketed antifungal small molecule, has been reported to possess anti-tumor activity through various mechanisms. Our preliminary screening of STING agonists revealed that ZPT could significantly induce STING activation. In this study, we investigated whether ZPT exerted anticancer effects as a small molecule activator of STING. We showed that ZPT bound to the STING protein in vitro with <i>K</i><sub>D</sub> value of 2.72 μM, and ZPT (1–16 μM) dose-dependently activated the STING-TBK1-IRF3 signaling axis in THP-1 cells. In MC38 tumor-bearing wild-type C57BL/6 mice with normal immune systems, administration of ZPT (5, 10, or 20 mg/kg, i.p., every two days for 14 days) dose-dependently inhibited the tumor growth, activated CD45<sup>+</sup>, CD3<sup>+</sup>, and CD8<sup>+</sup> T cells in both tumors and spleens, and significantly elevated IL-6 secretion in the peripheral blood. These results highlight the potential of ZPT as an immunotherapeutic agent targeting STING.</p><p></p>

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Zinc pyrithione functions as a small-molecule STING agonist to exert antitumor immunotherapy effects

  • 期刊论文

  • 发表日期：

    2025年10月17日

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  • Man Zhao,
  • Zu-yi Jin,
  • Wei-zhen Fan,
  • Peng-fei Qiang,
  • Zhi-hua Zheng,
  • Guo-feng Li,
  • Liang Hong,
  • Min Li

摘要

The stimulator of interferon genes (STING) is a crucial pattern recognition receptor that activates innate immunity, particularly in response to pathogen infection and various stimuli. Notably, activation of STING exhibits remarkable potential in enhancing anti-tumor immunity, underscoring the significance of discovering STING small molecule agonists. Recently, zinc pyrithione (ZPT), a marketed antifungal small molecule, has been reported to possess anti-tumor activity through various mechanisms. Our preliminary screening of STING agonists revealed that ZPT could significantly induce STING activation. In this study, we investigated whether ZPT exerted anticancer effects as a small molecule activator of STING. We showed that ZPT bound to the STING protein in vitro with KD value of 2.72 μM, and ZPT (1–16 μM) dose-dependently activated the STING-TBK1-IRF3 signaling axis in THP-1 cells. In MC38 tumor-bearing wild-type C57BL/6 mice with normal immune systems, administration of ZPT (5, 10, or 20 mg/kg, i.p., every two days for 14 days) dose-dependently inhibited the tumor growth, activated CD45+, CD3+, and CD8+ T cells in both tumors and spleens, and significantly elevated IL-6 secretion in the peripheral blood. These results highlight the potential of ZPT as an immunotherapeutic agent targeting STING.