Spatially Single-cell Protein Landscape Reveals the Distinct Tumor Microenvironment Architecture and Communications in Hepatocellular Carcinoma

Tumor microenvironment (TME) heterogeneity in hepatocellular carcinoma (HCC) on a spatial single-cell resolution remains unclearly. Here, we conducted co-detection by indexing (CODEX) to profile the spatial heterogeneity of 401 HCC samples with 36 biomarkers and determined 4,347,731 cells, 72 cell phenotypes (CP), and 40 cellular neighborhoods (CN). The synchronous activations of proliferation/hypoxia signal were presented in different CPs in certain CNs locally. Two mutually exclusive distributions (ring- or mosaic-like) were presented in different tumor cell-dominant CNs, of which mosaic-like enriches metabolic-related molecules. Five spatial patterns with distinct local CN compositions stratify clinical outcomes. Integration analysis with several independent cohorts revealed a novel Macrophage-Vimentin+ population could promote tumor progression and immune suppression via interacting with Tregs and triggering IL-1B expression. In light of immunotherapeutic data, our study provides novel insights into the influence of TME architecture on tumor evolution, reinforcing the necessity of spatial heterogeneity for developing personalized therapeutic strategies.