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

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

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.

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Fig. 1: ZPT is a novel non-nucleotide STING agonist.
Fig. 2: Differences in gene expression and enrichment of signaling pathway induced by ZPT.
Fig. 3: ZPT activates STING-TBK-IRF3 axis relying on STING and induces STING oligomerization.
Fig. 4: ZPT activates STING pathway in the form of pyridine-thione complex.
Fig. 5: ZPT reduces tumor burden in mice by activating the immune system.
Fig. 6: ZPT is a promising agent for tumor immunotherapy.
Fig. 7: ZPT increases infiltration of Treg cells in tumor tissues.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (32470793, 22271317), Guangdong Basic and Applied Basic Research Foundation (2025A1515011707), and the Shenzhen Medical Research Fund (SMRF) D2403008.

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Author notes

  1. These authors contributed equally: Man Zhao, Zu-yi Jin, Wei-zhen Fan

Authors and Affiliations

  1. State Key Laboratory of Anti-infective Drug Discovery and Development, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

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

  2. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China

    Man Zhao & Guo-feng Li

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Contributions

MZ, WZF, LH, and ML designed the research; MZ, ZYJ, and WZF performed the experiments; MZ and WZF analyzed the data; WZF and PFQ curated the data; ZYJ and PFQ developed the methodology; ZHZ, LH, and ML contributed to the conceptualization; MZ, ZYJ, WZF, PFQ, ZHZ, and ML wrote the paper; GFL, LH, and ML supervised the research; GFL, LH, and ML acquired the funding.

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Correspondence to Guo-feng Li, Liang Hong or Min Li.

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Zhao, M., Jin, Zy., Fan, Wz. et al. Zinc pyrithione functions as a small-molecule STING agonist to exert antitumor immunotherapy effects. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01674-9

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