The core obstacles and immunological mechanisms in the study of functional cure for Chronic Hepatitis B

Attaining a functional cure constitutes the paramount therapeutic objective in the management of chronic hepatitis B (CHB), as it markedly reduces the incidence of hepatocellular carcinoma and the progression to terminal liver disease. Despite this, the current functional cure rate among CHB patients remains below 30%. Major impediments to achieving this outcome include the persistent existence of viral covalently closed circular DNA (cccDNA), integration of the viral genome into the host’s DNA, immune tolerance resulting from prolonged exposure to elevated viral antigen levels, and host-mediated HBV-specific immune exhaustion and dysfunction at multiple regulatory levels. A thorough elucidation of the molecular pathways underpinning these barriers, alongside their associated immune regulatory networks, is critical for the advancement of novel therapeutic strategies. This review comprehensively integrates recent progress in understanding the virological mechanisms responsible for HBV persistence, host immune responses to HBV infection, and emerging immunotherapeutic interventions. The aim is to establish a theoretical foundation and provide critical perspectives to support the clinical translation of approaches designed to achieve a functional cure for CHB.