B cells in the progression from metabolic dysfunction-associated steatotic liver disease to hepatocellular carcinoma: immune regulation, microenvironmental crosstalk, and therapeutic implications.

Abstract

B cells exert stage-dependent and highly heterogeneous immunoregulatory functions throughout the progression from metabolic dysfunction-associated steatotic liver disease to hepatocellular carcinoma. Their functional states are shaped by disease stage, the metabolic milieu, and tissue-specific immune niches, thereby influencing hepatic inflammation, fibrotic remodeling, the tumor immune microenvironment, and responses to immunotherapy. During metabolic dysfunction-associated steatotic liver disease, particularly metabolic dysfunction-associated steatohepatitis, aberrantly activated B cells may promote hepatic inflammation through autoantibody production, secretion of pro-inflammatory cytokines, and antigen presentation. Alterations in the abundance or immunosuppressive activity of regulatory B cells may further disrupt local immune homeostasis. During liver fibrosis, B cells interact with macrophages, T cells, and hepatic stellate cells, contributing to extracellular matrix deposition and tissue remodeling. At the hepatocellular carcinoma stage, B cells display marked functional duality. Certain B-cell subsets support antitumor immunity by promoting the formation of tertiary lymphoid structures, whereas immunosuppressive B-cell subsets may impair CD8+ T-cell function, facilitate immune evasion, and promote tumor progression. This review summarizes the phenotypic characteristics, functional heterogeneity, and intercellular interactions of B cells throughout disease progression. It also discusses therapeutic strategies for modulating dysregulated B-cell states and integrating B-cell-targeted approaches with immunotherapy. Stratification by disease stage, etiology, and B-cell functional subset may support the development of precision therapeutic strategies.