Research Progress on Mechanisms of Immune Tolerance Induced by Hepatitis B Surface Antigen in Chronic HBV Infection

The sustained elevation of hepatitis B surface antigen (HBsAg) facilitates the progression of chronic hepatitis B virus (HBV) pathogenesis, and initiates and sustains host immune tolerance. Immune tolerance is a major factor contributing to viral persistence and viral clearance failure. HBsAg exerts regulatory effects on innate defenses and adaptive responses, limiting the activity of dendritic cells (DCs), natural killer (NK) cells, monocytes/macrophages, T lymphocytes, and B cells. Furthermore, it fosters a tolerogenic environment via interconnected regulatory cell networks, immune checkpoint molecules, and anti-inflammatory cytokines. HBsAg can enhance the intrahepatic immune-tolerant (IT) microenvironment by downregulating costimulatory molecules and promoting the secretion of immunosuppressive cytokines by intrahepatic nonparenchymal cells. This review systematically summarizes how HBsAg interferes with immune cell function and signaling pathways to establish a tolerogenic environment. We also cover recent progress in treatments that target HBsAg-induced immune tolerance. This review establishes a solid theoretical foundation and identifies new therapeutic approaches that can break tolerance to achieve a functional cure for chronic hepatitis B (CHB).