Tetrandrine activates STING/TBK1/IRF3 pathway, boosting anti-PD-1 efficacy in hepatocellular carcinoma models.

Hepatocellular carcinoma (HCC) remains a major global health burden with high mortality and limited effective treatments, especially for advanced or metastatic disease. Current first-line therapies, including programmed cell death protein 1 (PD-1) inhibitors, often face challenges like primary or acquired resistance, limiting their long-term efficacy. This resistance is frequently linked to an immunosuppressive tumor microenvironment. There's a critical need for novel strategies to enhance anti-PD-1 immunotherapy by modulating immune pathways and improving anti-tumor immunity.

Researchers investigated Tetrandrine (TET)'s impact on HCC and its synergy with anti-PD-1 therapy using both in vitro and in vivo models. In vitro, STING was knocked down in HCC cells, which were then co-cultured with activated CD8+ T cells extracted from peripheral blood. TET was added to this system to evaluate its effects on HCC malignant behavior and CD8+ T cell activation. DNA damage markers like γ-H2AX and dsDNA were detected via immunofluorescence and Western blot. Molecular docking predicted TET's interaction with STING/TBK1/IRF3 pathway proteins, with pathway activation confirmed by Western blot. In vivo, subcutaneous and orthotopic HCC models were established in mice. The therapeutic effects of TET combined with anti-PD-1 were assessed by tumor volume, histopathological analysis, and immunohistochemistry. Serum biochemical indicators were measured for safety.

Tetrandrine (TET) demonstrated a multifaceted anti-tumor effect. It significantly inhibited HCC growth and induced apoptosis in vitro. TET also promoted CD8+ T cell activation, proliferation, and cytotoxicity, enhancing their ability to secrete IFN-γ and TNF-α. Mechanistically, TET induced DNA damage and dsDNA accumulation, leading to the activation of the STING/TBK1/IRF3 signaling pathway. STING knockdown experiments confirmed that this pathway was central to TET's anti-cancer effects. Molecular docking further supported TET's interaction with key proteins in this pathway. > In vivo, the combination of TET and anti-PD-1 produced a significant synergistic anti-tumor effect, effectively inhibiting HCC growth and increasing CD8+ T cell infiltration in both subcutaneous and orthotopic mouse models. Importantly, this combination significantly improved liver and kidney function indicators, with no obvious toxic reaction observed, suggesting a favorable safety profile.