Navigating the immunometabolic heterogeneity of B cells in murine hepatocellular carcinoma at single cell resolution

Induction of antitumor immunity is critical for the therapeutic efficacy of hepatocellular carcinoma (HCC) immunotherapy. The cellular metabolic state underpins the effector function of immune cells, yet our understanding of the phenotypic and metabolic heterogeneity of B cells within HCC microenvironment is poorly developed. Herein, we investigated the composition, distribution, phenotype, function and metabolic profiles of B-cell subsets in HCC and adjacent liver tissues from an orthotopic HCC mouse model using single-cell RNA sequencing (scRNA-seq). Our results identified six B-cell clusters, which can be classified into plasma cells and activated and exhausted B cells according to marker expression, functional and temporal distribution. Exhausted B cells exhibited low metabolic activities and impaired effector functions. Activated B and plasma cells showed higher metabolic activity than exhausted B cells, but there were clear differences in their metabolic profiles. In addition, we found that the effector function of exhausted B cells was further diminished in HCC tissues compared with adjacent liver tissues, but their metabolic activity was significantly enhanced. Collectively, we comprehensively characterized the metabolic profile and alterations in B-cell subsets in HCC, which contributes to the understanding of B-cell immunology in HCC and lays the foundation for exploring novel targets in HCC immunotherapy.