A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity
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 resistan...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07578-0 |
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| author | Xuemei Liu Hongbin He Minghui Qi Zhongjun Jiang Bolong Lin Xiaqiong Wang Di Wang Ming Ma Wei Jiang Rongbin Zhou |
| author_facet | Xuemei Liu Hongbin He Minghui Qi Zhongjun Jiang Bolong Lin Xiaqiong Wang Di Wang Ming Ma Wei Jiang Rongbin Zhou |
| author_sort | Xuemei Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ab5bd3f921eb4205ab2b838d80d5d3a7 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ab5bd3f921eb4205ab2b838d80d5d3a72025-08-20T03:04:53ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111010.1038/s41419-025-07578-0A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunityXuemei Liu0Hongbin He1Minghui Qi2Zhongjun Jiang3Bolong Lin4Xiaqiong Wang5Di Wang6Ming Ma7Wei Jiang8Rongbin Zhou9National 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 ChinaNational 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 ChinaNational 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 ChinaNational 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 ChinaNational 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 ChinaNational 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 ChinaInstitute of Immunology, Zhejiang University School of MedicineNational 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 ChinaNational 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 ChinaNational 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 ChinaAbstract 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.https://doi.org/10.1038/s41419-025-07578-0 |
| spellingShingle | Xuemei Liu Hongbin He Minghui Qi Zhongjun Jiang Bolong Lin Xiaqiong Wang Di Wang Ming Ma Wei Jiang Rongbin Zhou A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity Cell Death and Disease |
| title | A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity |
| title_full | A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity |
| title_fullStr | A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity |
| title_full_unstemmed | A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity |
| title_short | A small molecule directly targets NLRP3 to promote inflammasome activation and antitumor immunity |
| title_sort | small molecule directly targets nlrp3 to promote inflammasome activation and antitumor immunity |
| url | https://doi.org/10.1038/s41419-025-07578-0 |
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