Single-Cell Transcriptomic Profiling Reveals Immunometabolic Reprogramming and Cell-Cell Communication in the Tumor...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Hepatocellular carcinoma (HCC) growth involves intricate crosstalk between malignant hepatocytes, immune cells, and stromal components.
• Tumor progression is characterized by immune evasion and vascular remodeling, driven by these cellular interactions.

Purpose of the Study:

• To characterize cell-type-specific transcriptional programs in HCC.
• To reconstruct intercellular communication circuits within the tumor microenvironment.
• To identify cooperative immunometabolic modules as potential therapeutic targets.

Main Methods:

• Integrative single-cell transcriptomics on 93,032 cells from human HCC tumors and healthy liver.
• Analysis of cell-type-specific gene expression, focusing on metabolic and immune pathways.
• Ligand-receptor inference to map intercellular communication networks.

Main Results:

• Malignant hepatocytes exhibit metabolic plasticity (glycolysis and OXPHOS) and suppressed antigen presentation.
• Tumor-associated macrophages show immunosuppressive phenotypes with TREM2 enrichment and lipid handling.
• Tumor endothelial cells upregulate pro-angiogenic and ECM programs while downregulating innate immunity.
• Intercellular communication shifts from antigen presentation in healthy liver to pro-angiogenic, ECM, chemokine, and lipid signaling in HCC.

Conclusions:

• HCC progression is an emergent property of a stabilized multicellular network, not solely autonomous cancer cell behavior.
• A rewiring of intercellular communication networks, dominated by malignant hepatocytes, TAMs, and TECs, sustains the tumor microenvironment.
• Cooperative immunometabolic modules within this network represent tractable targets for combination therapies.