& nbsp;Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous hepatocellular carcinoma

Scirrhous hepatocellular carcinoma (SHCC) is one of the unique subtypes of hepatocellular carcinoma (HCC), characterized by abundant fibrous stroma in tumor microenvironment. However, it remains unclear about the molecular traits of SHCC, which is essential to develop specialized therapeutic approaches for SHCC.We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients, to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC. Multiplexed immunofluorescence staining, flow cytometry, and functional experiments were performed for validation. Here, we identified SHCC presented with less genomic heterogeneity while possessed a unique transcriptomic profile different from usual HCC. Insulin-like growth factor 2 (IGF2) was significantly upregulated in SHCC tumor cells comparing to usual HCC, and could serve as a potential diagnostic biomarker for SHCC. Significant tumor stromal remodeling and hypoxia were observed in SHCC with enrichment of matrix cancer-associated fibroblasts and upregulation of hypoxic pathways. And IGF2 was identified as a key mediator in shaping the hypoxic stromal microenvironment of SHCC. Under this microenvironment, SHCC exhibited an immunosuppressive niche correlated to enhanced vascular-endothelial-growth-factor A signaling activity, where CD4+T cells and CD8+T cells were dysfunctional. Furthermore, we found another hypoxic-related molecule SPP1 from SHCC tumor cells suppressed the function of dendritic cells via SPP1-CD44 axis, which also probably hindered the activation of T cells.We uncovered the genomic characteristics of SHCC, and revealed a hypoxia-driven tumor stroma remodeling and immunosuppressive microenvironment in SHCC.