From virological selection to immune stratification: Hepatitis B virus-specific T cells for precision pegylated interferon therapy in chronic hepatitis B

Pegylated interferon (PEG-IFN) alpha, an important agent for chronic hepatitis B (CHB), exerts antiviral and immunomodulatory activities and serves as a core therapy to pursue functional cure. However, there are significant individual differences in treatment response, and the lack of reliable patient-selection strategies remains a major limitation to clinical application. Recent studies have shown that hepatitis B virus (HBV)-specific T cells are the core effector cells mediating viral clearance and maintaining immune control, and that the degree of their functional restoration is closely related to responses to PEG-IFN treatment and hepatitis B surface antigen clearance. In chronic HBV infection, HBV-specific T cells generally exhibit characteristics such as reduced numbers, functional exhaustion, metabolic abnormalities, and epigenetic remodeling. PEG-IFN can achieve immune remodeling by enhancing HBV-specific T cell responses, promoting the formation of memory-like T cells, improving multifunctional effector functions, and partially reversing the exhausted state. This review summarizes HBV-specific T cell dysfunction in chronic HBV infection, PEG-IFN-mediated immune remodeling mechanisms and relevant biomarker advances, to discuss the value of these T cells for precise interferon candidate screening and immune-stratified therapy. Such indicators may transform CHB management from virology-based to immunology-guided strategies and support precision treatment toward functional cure.