Interferon-α for Immune Modulation in Chronic Hepatitis B Toward Functional Cure

Chronic hepatitis B (CHB) remains a major global health challenge, largely due to the persistence of covalently closed circular DNA (cccDNA) and impaired host immunity. Interferon-α (IFN-α), a key antiviral cytokine, not only directly restricts HBV replication but also orchestrates innate and adaptive immune responses. This review summarizes current advances in IFN-α-mediated immune regulation, highlighting its effects across diverse immune cell populations. Evidence indicates that IFN-α can reprogram immune responses to promote viral clearance, although clinical efficacy is limited by modest response rates and adverse effects. Recent progress in cytokine engineering, subtype research, and rational combination strategies-including nucleo(s/t)ide analogs, RNA interference therapeutics, antisense oligonucleotides, therapeutic vaccines, and beyond-has expanded opportunities to improve treatment outcomes. While challenges remain, these advances lay the foundation for optimizing IFN-α-based interventions and highlight IFN-α as a key driver for innovative therapies aimed at achieving a functional cure of chronic hepatitis B.