Single-cell analyses of liver and blood reveal distinct immune cell signatures of HBV-related HCC patients

Chronic hepatitis B virus (HBV) infection is a major etiological driver of hepatocellular carcinoma (HCC) and is accompanied by profound immune dysregulation that shapes disease progression and therapeutic responsiveness. However, the extent to which systemic immunity reflects the tumor immune microenvironment (TIME) in HBV-related HCC (HBV-HCC) remains incompletely defined. Here, we used mass cytometry (CyTOF) to resolve immune heterogeneity across peripheral blood mononuclear cells (PBMCs), tumor tissues, and matched adjacent non-tumor (paracancer) tissues in treatment-naïve HBV-HCC. PBMCs, tumor tissues, and paracancer tissues were collected from 12 treatment-naïve HBV-HCC patients and profiled by CyTOF. Nine major immune lineages/clusters were quantified and compared across compartments. Immune-cell distributions were correlated with virological and clinicopathological features (HBV DNA status, serum alpha-fetoprotein [AFP], tumor differentiation) and 5-year clinical outcomes. Public transcriptomic datasets were further leveraged for external validation of CD8A/CD8B-associated prognostic signals. HBV-HCC exhibited marked systemic-local immune compartmentalization. PBMCs were enriched for naïve CD8⁺ T cells and natural killer (NK) cells, whereas paracancerous tissues showed higher abundance of myeloid-derived suppressor cells (MDSCs) and memory CD8⁺ T cells. In contrast, HCC tissues were characterized by increased neutrophils and regulatory T (Treg) cells, together with a more activated and immunosuppressive marker profile in HCC-associated MDSCs. HBV DNA-positive patients showed higher intratumoral expression of naïve CD8⁺ T cells and Tregs than HBV DNA-negative patients, with the increase being most evident in HCC tissues relative to matched paracancerous tissues. Clinically aggressive phenotypes, including high AFP, poor differentiation, and postoperative recurrence, were characterized by neutrophil expansion accompanied by reduced PD-1⁺ dendritic cells (PD-1⁺ DCs) and decreased naïve/memory CD8⁺ T-cell subsets. Although higher CD8A/CD8B expression in public datasets predicted improved survival, CyTOF indicated that abundant intratumoral CD8⁺ infiltration could coexist with systemic and intratumoral immunosuppression and functional exhaustion, consistent with the recognized challenge of reinvigorating exhausted intrahepatic immunity. HBV-HCC is defined by profound immune heterogeneity across blood, tumor, and adjacent non-tumor compartments. Distinct immune signatures associate with virological activity, tumor aggressiveness, and long-term outcomes, providing a rationale for immune-based patient stratification and for combinatorial immunotherapy strategies targeting both myeloid-driven suppression and dysfunctional T-cell immunity.