GPNMB⁺Gal-3⁺ hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis

Hepatocellular carcinoma (HCC) formation is a multi-step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single-cell transcriptome sequencing was applied to profile rat models of toxin-induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta), Epcam(+) population with differentiation potential (EP+Diff) and immunosuppressive malignant transformation subset (MTImmu). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu. Importantly, GPNMB(+)Gal-3(+) MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB(+)Gal-3(+) MTImmu cells. Enrichment of the GPNMB(+)Gal-3(+) MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single-cell HCC progression atlas and uncovered GPNMB(+)Gal-3(+) parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.