Single-cell RNA sequencing reveals a reprogramming of hepatic immune cells and a protective role for B cells in MASH-driven HCC.

Background: HCC, the most common form of liver cancer, is one of the leading causes of cancer-related deaths worldwide. Although the immune system plays a crucial role in liver cancer pathogenesis, the immune landscape within metabolic dysfunction-associated steatohepatitis-driven HCC remains poorly understood.

Methods: In this study, we used the high-fat, high-carbohydrate diet fed major urinary protein-urokinase-type plasminogen activator mouse model of metabolic dysfunction-associated steatohepatitis-driven HCC. We performed single-cell RNA sequencing on intrahepatic immune cells to characterize their heterogeneity and gene expression profiles. Additionally, we examined the role of B cells in antitumor immunity by depleting B cells in μMT mice and analyzing the effects on liver cancer progression.

Results: Our analysis revealed significant shifts in intrahepatic immune cell populations, including B cells, T cells, and macrophages that undergo transcriptional reprogramming, suggesting altered roles in tumor immunity. Notably, an expanded subset of activated B cells in HCC mice showed an antitumor B cell gene expression signature associated with increased survival of patients with liver cancer. Consistently, B cell-deficient mice showed exacerbated liver cancer progression, a substantial reduction in intrahepatic lymphocytes, and impaired CD8+ T cell activation, suggesting that intrahepatic B cells may promote antitumor immunity by enhancing T cell responses.

Conclusions: Our findings reveal a complex immune reprogramming within the metabolic dysfunction-associated steatohepatitis-driven HCC microenvironment and underscore a protective role for B cells in liver cancer. These results highlight B cells as potential targets for immunomodulatory therapies in HCC.