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

Hepatic carcinoma, one of the most malignant cancer in the world, has limited success immunotherapy in patients and poor prognosis. Pyroptosis while thinking as promising immunotherapy strategy for tumors, still suffers from the lack of effective inducers. Here, we designed, synthesized and screened an indole analogue Tc3 featuring a 2, 4-thiazolidinedione substituted indole scaffold. Treatment of Tc3 could notably inhibit the growth of hepatic carcinoma in vitro and in vivo. Mechanistically, Tc3 induced GSDME-mediated pyroptosis by activating the endoplasmic reticulum stress kinase PERK. Tumor cells with high expression of GSDME achieved better responses to Tc3-therapy. Tc3 improved efficacy of cisplatin of hepatic carcinoma. Additionally, the superior synergistic treatment was also exhibited via combined Tc3 with PD-1 antibodies. It is noteworthy that Tc3 could activate tumor immune microenvironment (TIME) and enhanced CD8+ T cell infiltration of hepatic carcinoma. Collectively, our findings identified a promising and effective compound Tc3 for treating hepatic carcinoma and identified its synergy therapeutic strategy as a pyroptosis inducer.