Chronic Hepatitis B: Current Understanding and Clinical Implications of Immune Exhaustion

Chronic hepatitis B (CHB) infection leads to progressive dysfunction and exhaustion of antiviral immune cells, which is a primary obstacle to clinical cure. Although the phenotypic hallmarks of exhausted T cells are well described, the hierarchical trajectory, subset-specific heterogeneity, and underlying mechanisms of exhaustion across the full spectrum of immune cells in the unique hepatic microenvironment remain poorly defined. This review provides a comprehensive and critical synthesis of recent advances in immune exhaustion during CHB. We delineate the common and distinct exhaustion programs among T, B, and natural killer cells, highlighting the pivotal roles of transcription factors and metabolic dysregulation. Furthermore, we critically evaluate the limitations of current evidence and pinpoint critical knowledge gaps, such as the heterogeneity of non-classical exhausted subsets and the liver-resident immune compartment. By framing these findings within a critical and comparative context, this review not only updates our understanding of immune exhaustion but also proposes a roadmap for developing more precise immunotherapies aimed at achieving a functional cure for CHB.