Single-Cell Transcriptomic Profiling Reveals Immunometabolic Reprogramming and Cell-Cell Communication in the Tumor Microenvironment of Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is driven by coordinated interactions among malignant hepatocytes, immune cells, and stromal populations that collectively sustain tumor growth, immune evasion, and vascular remodeling. Through integrative single-cell transcriptomic analysis of 159,925 cells from tumor and healthy human liver tissues, we delineated the cell-type-specific transcriptional programs underlying immunometabolic reprogramming and mapped the intercellular communication circuits that maintain tumor homeostasis. Malignant hepatocytes activated dual glycolytic and oxidative metabolic programs while suppressing antigen presentation capacity, coupling metabolic plasticity to immune evasion. Tumor-associated macrophages acquired TREM2-enriched, lipid-handling phenotypes consistent with immunosuppressive polarization, and tumor endothelial cells upregulated angiocrine and extracellular matrix programs while silencing innate immune outputs. Ligand–receptor inference revealed a qualitative rewiring of intercellular communication: the antigen-presentation-centered network of healthy liver was replaced by a tumor-driven architecture dominated by pro-angiogenic, ECM-integrin, inflammatory chemokine, and lipid-associated signaling circuits, with malignant hepatocytes, TAMs, and TECs collectively assuming the dominant signaling burden. These findings establish that HCC progression is an emergent property of a stabilized multicellular network rather than the autonomous behavior of malignant cells, and define cooperative immunometabolic modules that constitute tractable targets for combinatorial therapeutic intervention.