Single-cell and spatial atlas of steatotic liver disease-related hepatocellular carcinoma

Summary Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC) poses significant challenges in liver cancer management. Our current study investigates the tumor microenvironment (TME) of SLD-HCC using single-cell transcriptomic, proteomic and spatial transcriptomic analyses. We identified altered immune-related and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) within the SLD-HCC microenvironment, suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. Cytometry by time-of-flight revealed a cold and immunosuppressive TME depleted with CD8 + T cells and enriched with Tregs, while spatial transcriptomics uncovered a unique spatial architecture with Treg/CAF clusters specifically located at the tumor margins in SLD-HCC. Crucially, we identified Treg-CAF interactions as a key mediator associated with lack of response to immunotherapy in SLD-HCC. Our findings highlight the intricate immune dynamics of SLD-HCC, indicating potential therapeutic targets to counteract immune evasion and restore anti-tumor immunity in SLD-HCC. Highlights The TME of SLD-HCC exhibits altered immune and lipid pathways Immunosuppressive SLD-HCC TME is depleted with CD8 + T cells and enriched with Tregs SLD-HCC has a unique spatial architecture with Treg-CAF clusters at tumor margins Treg-CAF interaction via TNFSF14-TNFRSF14 axis mediates immunotherapy resistance