Single-Cell and Spatial Transcriptomics Unveil M-MDSC–Tumor Crosstalk Driving EMT in HCC via THBS1-SDC4 Axis

The induction and accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs) have been confirmed extensively in hepatocellular carcinoma (HCC), but the mechanism of this activation is not fully resolved and might underlie immunotherapy resistance. Here, single-cell and spatial transcriptomics reveal that matrix CAFs (mCAFs) regulate M-MDSCs to promote epithelial-mesenchymal transition (EMT) in HCC. Intercellular communication analyses suggest that M-MDSCs influence tumor biology by secreting thrombospondin 1(THBS1), which interacts with syndecan-4 (SDC4) on tumor cells. Subsequent in vitro and in vivo experiments confirm that SDC4 enhances malignant tumor behavior. Finally, NCG tumor mouse models demonstrate that M-MDSCs drive tumor EMT via THBS1-SDC4 trans-cellular signaling, highlighting a potential immunotherapy strategy for HCC.