Oxaliplatin induces pyroptosis in hepatoma cells and enhances antitumor immunity against hepatocellular carcinoma.

Background: Pyroptosis is closely associated with chemotherapeutic drugs and immune response. Here, we investigated whether oxaliplatin, a key drug in FOLFOX-hepatic artery infusion chemotherapy (FOLFOX-HAIC), induces pyroptosis in hepatoma cells and enhances antitumor immunity after tumor cell death.

Methods: Hepatoma cells were treated with oxaliplatin. Pyroptosis and immunoreactivity were evaluated in vitro and in vivo.

Results: Oxaliplatin activated caspase-3-mediated gasdermin E (GSDME) cleavage and induced pyroptosis in Hep G2 and SK-Hep-1 cells in vitro. Liver cancer cells with high levels of GSDME expression are prone to pyroptosis. Bioinformatic analysis revealed that pyrolysis-related genes are closely related to immunity. In vivo experiments revealed that oxaliplatin exhibited superior antitumor efficacy in mice with normal immune function and more pronounced inhibitory effect on hepatocellular carcinoma with high GSDME levels. Higher levels of cytokines and greater CD8⁺ T cell infiltration were observed in tumor tissues with better efficacy. Furthermore, an in vitro coculture assay confirmed that oxaliplatin-induced pyroptosis in Hep G2 cells overexpressing GSDME and activated the p38/MAPK signaling pathway to improve the cytotoxicity of CD8⁺ T cells. Analysis of clinical samples of HCC suggested that the efficacy of FOLFOX-HAIC in patients with high GSDME expression was better than that in patients with low GSDME expression.

Conclusions: Oxaliplatin induced pyroptosis in hepatoma cells by activating caspase-3-mediated cleavage of GSDME, which enhanced the cytotoxicity of CD8⁺ T cells by regulating the p38/MAPK signaling pathway. These results suggest that GSDME level may be used as a marker to predict the efficacy of FOLFOX-HAIC.