From exhaustion to functional cure: frontiers in reversing HBV-specific T-cell immunity

Chronic hepatitis B (CHB) remains a leading cause of liver-related morbidity and mortality, affecting approximately 254 million people worldwide and accounting for more than 800,000 deaths annually. Although nucleos(t)ide analogues (NAs) durably suppress viral replication, the annual rate of HBsAg loss is only ~1%, leaving functional cure as the foremost unmet clinical need. Exhaustion of HBV-specific CD8⁺ T cells is now widely accepted as the central immunological barrier to viral clearance. Single-cell sequencing, spatial transcriptomics and epigenome profiling have collectively redefined this state: T-cell dysfunction in CHB is not a uniform "exhaustion phenotype" but a profoundly heterogeneous condition reinforced at transcriptional, epigenetic, metabolic and microenvironmental levels. In this review, we dissect the molecular signatures and inter- and intra-patient heterogeneity of HBV-specific T-cell exhaustion, with emphasis on the exhaustion programmes orchestrated by TOX, NFAT and NR4A factors, the epigenetic "lock-in" imposed by DNA methylation and histone modifications, and the bioenergetic insufficiency that arises from mitochondrial dysfunction. We then critically evaluate current reversal strategies, including immune checkpoint blockade (ICB), epigenetic modulators, engineered cytokines, microenvironment-directed agents (notably the ECM1-latent TGF-β axis), metabolic rewiring, and CAR-T/TCR-T cell therapy. Particular attention is given to the 2024 landmark studies that reshaped the conceptual landscape of the field - 4-1BB/OX40 co-stimulation, the hepatic immune rheostat, and attenuated effector T cells. We argue that no single intervention will suffice; only combinatorial regimens that simultaneously unlock epigenetic constraints, restore metabolic fitness, relieve checkpoint suppression and remodel the hepatic microenvironment can realistically advance HBV functional cure. This review is intended as a mechanism-grounded yet translationally oriented reference for both basic immunologists and hepatologists.