A Pan-Hepatic T-Cell Atlas Identifies Disease-Specific Immune Dysfunction and Therapeutic Targets for Immunotherapy

Single-cell transcriptomics has greatly advanced insight into hepatic immunity and immunotherapy. However, the absence of an integrated atlas spanning multiple hepatic diseases limits systematic comparisons of immune heterogeneity and dynamics. Here, we established a Pan-HEpatic single-cell Atlas of T cells (Pheat), covering 139 donors, 255 blood and liver samples spanning chronic hepatitis (chronic hepatitis B/C [CHB/CHC], alcohol-associated hepatitis, metabolic dysfunction-associated steatohepatitis), cirrhosis, hepatocellular carcinoma (HCC), and healthy controls (HC), and delineated profound population-, tissue-, and disease-level heterogeneity of 624,215 T cells, with emphasis on CD8⁺ exhausted T cells (Tex) and CD4⁺ regulatory T cells (Treg). Within Tex, intrahepatic precursor Tex (Tex^pre) were depleted in CHB compared with healthy controls and other hepatic diseases. Disease-specific checkpoint dominance (4-1BB in CHB, TIGIT in HCC) in Tex^pre was identified and experimentally validated. Panobinostat was predicted and validated to reinvigorate Tex^pre in CHB patients. In parallel, effector Treg (eTreg) accumulated in diseased livers and exhibited divergent IL-2-STAT5 signaling-hyperactive in CHB and HCC, suppressed in cirrhosis-indicating distinct immunosuppressive status. Lapatinib/olopatadine enhanced Treg suppressive markers in cirrhosis. Pheat provides a high-resolution atlas of hepatic T cells, revealing disease-specific immune heterogeneity and regulatory programs that inform cellular and molecular targets for potential immunotherapy.