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

  • Acta Pharmacol Sin. 2025 Oct 17. doi: 10.1038/s41401-025-01674-9.
Man Zhao  #  1  2 ,  Zu-Yi Jin  #  1 ,  Wei-Zhen Fan  #  1 ,  Peng-Fei Qiang  1 ,  Zhi-Hua Zheng  1 ,  Guo-Feng Li  3 ,  Liang Hong  4 ,  Min Li  5
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.
  • 2. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China.
  • 3. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China. [email protected].
  • 4. 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. [email protected].
  • 5. 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. [email protected].
  • # Contributed equally.
PMID: 41107405 DOI: 10.1038/s41401-025-01674-9
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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