Discovery of indole analogue Tc3 as a potent pyroptosis inducer and identification of its combination strategy against hepatic carcinoma.

Hepatic carcinoma, one of the most malignant cancers in the world, has limited success with immunotherapy and a poor prognosis in patients. While pyroptosis is considered as a promising immunotherapy strategy for tumors, it still suffers from a lack of effective inducers. We designed, synthesized and screened an indole analogue, , featuring a 2, 4-thiazolidinedione substituted indole scaffold. Western blotting, qPCR and immunofluorescence were employed to detect the levels of pyroptosis pathway induced by . RNA sequencing was used to identify the mechanisms of in hepatic carcinoma. To validate anti-tumor effect of , we used CDXs and PDXs mouse models . Then, the syngeneic effects of with cisplatin and anti-PD-1 antibody were verified via western blotting, immunofluorescence, flow cytometry and ELISA. Treatment with notably inhibited the growth of hepatic carcinoma both and . Mechanistically, inhibited the function of PRDX1 and up-regulated excessive ROS. Then, induced gasderminE-mediated pyroptosis by activating the endoplasmic reticulum stress. Tumor cells with high expression of GSDME achieved better responses to -therapy. also improved the efficacy of cisplatin against hepatic carcinoma. Additionally, superior synergistic treatment was observed when was combined with anti-PD-1 antibody. Notably, activated the tumor immune microenvironment (TIME) and enhanced CD8 T cell infiltration in hepatic carcinoma. Collectively, we identified as a promising and effective compound for treating hepatic carcinoma and established its synergistic therapeutic strategy as a pyroptosis inducer.