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 (HC^Meta ), Epcam⁺ population with differentiation potential (EP^+Diff ) and immunosuppressive malignant transformation subset (MT^Immu ). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP^+Diff to MT^Immu . Importantly, GPNMB⁺ Gal-3⁺ MT^Immu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB⁺ Gal-3⁺ MT^Immu cells. Enrichment of the GPNMB⁺ Gal-3⁺ MT^Immu 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.