Tetrandrine enhances anti-PD-1 immunotherapeutic efficacy for hepatocellular carcinoma by activating STING/TBK1/IRF3 pathway

Introduction Hepatocellular carcinoma (HCC) remains a significant global public health risk, and its mortality rate remains high. Tetrandrine (TET) inhibits tumor growth, but its combination with anti-PD-1 immunotherapy has not been fully elucidated. Methods STING was knocked down in HCC cells, and CD8 + T cells were extracted and activated from peripheral blood. CD8 + T cells were co-cultured with HCC cells, and TET was added. This study evaluated TET’s effects on HCC malignant behavior and CD8 + T cell activation in the co-culture system. γ-H2AX and dsDNA were detected through immunofluorescence and Western blot. The interaction between TET and the proteins of STING/TBK1/IRF3 pathway was predicted by molecular docking, and the activation of this pathway was analyzed by Western blot. Subcutaneous and orthotopic HCC models were established in mice. The therapeutic effects of TET+anti-PD-1 were evaluated by tumor volume measurement, histopathological analysis and immunohistochemistry, and serum biochemical indicators were detected for safety evaluation. Results TET significantly inhibited HCC growth and induced apoptosis. It also promoted CD8 + T cell activation, proliferation and cytotoxicity, and enhanced their ability to secrete IFN-γ and TNF-α. TET also induced DNA damage and dsDNA accumulation, and activated STING/TBK1/IRF3 signal. STING knockdown experiments confirmed that this pathway was central for TET anti-cancer effects. In addition, TET and anti-PD-1 produced a significant synergistic anti-tumor effect, effectively inhibited HCC growth, increased CD8 + T cell infiltration, and significantly improved liver and kidney function indicators. No obvious toxic reaction was observed. Discussion By activating STING/TBK1/IRF3 signaling, TET enhanced CD8 + T cell-mediated anti-tumor immunity, thereby markedly enhancing anti-PD-1 therapy efficacy in HCC.