The role of HBV in reprogramming liver cancer stem cells and shaping their plasticity and therapeutic vulnerabilities.

Hepatitis B virus (HBV) infection remains a leading cause of hepatocellular carcinoma (HCC) worldwide, particularly in East Asia. Liver cancer stem cells (LCSCs) have emerged as crucial drivers of HCC initiation, metastasis, recurrence, and therapeutic resistance. Accumulating evidence indicates that HBV, especially through its X protein (HBx), promotes LCSC formation and maintenance via activation of multiple oncogenic and stemness-related signaling pathways, including IL-6/STAT3, Wnt/β-catenin, Hippo, and Notch. Furthermore, HBV infection induces cellular plasticity through epithelial-mesenchymal transition (EMT), dedifferentiation, and metabolic reprogramming, facilitating the acquisition of stem-like phenotypes. Within the immunosuppressive tumor microenvironment shaped by chronic HBV infection, LCSCs gain enhanced immune evasion capabilities and interact with immune cells to sustain their niche. These interactions, coupled with metabolic and epigenetic alterations, underlie the profound resistance of LCSCs to conventional therapies. This review summarizes the current understanding of the molecular crosstalk between HBV infection and LCSC regulation, highlighting key pathways and mechanisms. We also discuss emerging therapeutic strategies targeting HBV-driven LCSCs, including combined antiviral and immunotherapy approaches, and underscore the need for further translational studies to improve outcomes in HBV-associated HCC.