A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity

  • Cell Death Dis. 2025 Apr 4;16(1):252. doi: 10.1038/s41419-025-07578-0.
Xuemei Liu  1 ,  Hongbin He  1 ,  Minghui Qi  1 ,  Zhongjun Jiang  1 ,  Bolong Lin  1 ,  Xiaqiong Wang  1 ,  Di Wang  2 ,  Ming Ma  3 ,  Wei Jiang  4 ,  Rongbin Zhou  5
Affiliations
  • 1. National Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. National Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 4. National Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 5. National Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
PMID: 40185713 DOI: 10.1038/s41419-025-07578-0
Abstract

Immune checkpoint blockade (ICB) therapies have emerged as promising treatment of Cancer, but the efficacy is limited. NLRP3 inflammasome activation in tumor microenvironment can promote the infiltration of cytotoxic lymphocytes and antitumor immunity, but it is unclear whether ICB resistance can be overcome by directly targeting NLRP3. Here we show that a small molecule compound directly targeting NLRP3 can induce inflammasome activation and anti-tumor immunity. 2-guanidinobezimidazole (2GBI) directly bound to NLRP3 and induced inflammasome activation, which was independent of potassium efflux, chloride efflux and mitochondrial dysfunction. 2GBI treatment alone promoted anti-tumor immunity and inhibited tumor growth via NLRP3-dependent manner. Moreover, 2GBI treatment could overcome ICB resistance and exerted synergistic anti-tumor effects. These results suggest that targeting NLRP3 is a potential strategy to induce anti-tumor immunity and improve the efficacy of ICB.

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