Oxymatrine Inhibits PD-L1 by Downregulating IFN-γ to Promote Ferroptosis and Enhance Anti-PD-L1 Efficacy in Liver Cancer.

Purpose: Oxymatrine has potent anti-cancer activity, but its exact mechanism in liver cancer remains elusive. The present study was designated to explore oxymatrine's effect and the potential mechanism on Programmed cell death-ligand 1 (PD-L1) expression and ferroptosis in liver cancer.

Methods: Oxymatrine's influence on PD-L1 expression and ferroptosis-related proteins in liver cancer cells was explored in vitro and in vivo utilizing Western blotting, qRT-PCR, immunofluorescence, ELISA, H&E staining, immunohistochemistry, as well as detection of Fe²⁺, ROS, and MDA.

Results: The in-vivo results showed that xenotransplanted tumor mice with drug interventions (oxymatrine, anti-PD-L1, and combination groups) exhibited inhibited tumor growth compared to control mice. Relative to anti-PD-L1 administration alone, the combined treatment inhibited tumor growth more significantly, along with reduced interferon-γ (IFN-γ) expression in peripheral blood and remarkably increased tumor immune lymphocyte (CD4⁺ T and CD8⁺ T) infiltration in cancer tissues. Meanwhile, PD-L1, xCT, and GPX4 protein levels in the combination group were significantly downregulated. According to the in vitro results, IFN-γ promoted PD-L1, xCT, and GPX4 protein levels in liver cancer cell lines. Oxymatrine reversed IFN-γ-induced upregulation of PD-L1 expression; moreover, it downregulated xCT and GPX4 protein levels in liver cancer cells and promoted intracellular Fe²⁺, ROS, and MDA levels.

Conclusion: Oxymatrine promotes tumor immune response and ferroptosis in liver cancer by downregulating IFN-γ and synergistically enhances the inhibitory effect of anti-PD-L1 on liver cancer.