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

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.