Berberine Protects against Hepatocellular Carcinoma Progression by Regulating Intrahepatic T Cell Heterogeneity

Accumulating evidence suggests that berberine (BBR) exhibits anti-cancer effects in hepatocellular carcinoma (HCC). However, the mechanisms by which BBR regulates the immunological microenvironment in HCC has not been fully elucidated. In this study, a mouse model of orthotopic HCC is established and treated with varying doses of BBR. BBR showed effectiveness in reducing tumor burden in mice with HCC. Cytometry by time-of-flight depicted the alterations in the tumor immune landscape following BBR treatment, revealing the enhancement in the T lymphocytes effector function. In particular, BBR decreased the proportion of TCRb^hiPD-1^hiCD69⁺CD27⁺ effector CD8⁺ T lymphocytes and increased the proportion of Ly6C^hiTCRb⁺CD69⁺CD27⁺CD62L⁺ central memory CD8⁺ T lymphocytes. Single-cell RNA sequencing further elucidates the effects of BBR on transcriptional profiles of liver immune cells and confirms the phenotypical heterogeneity of T lymphocytes in HCC immune microenvironment. Additionally, it is found that BBR potentially regulated the antitumor immunity in HCC by modulating the receptor-ligand interaction among immune cells mediated by cytokines. In summary, the findings improve the understanding of BBR's impact on protecting against HCC, emphasizing BBR's role in regulating intrahepatic T cell heterogeneity. BBR has the potential to be a promising therapeutic strategy to hinder the advancement of HCC.