Background and Aims:Oncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here, we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs.Approach and Results:OSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild-type and hepatocyte-specific OSM receptor-beta (hOSMR beta-/-) deficient mice, and in vitro experiments performed on liver cancer and immune cell lines. Analysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMR beta-/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMR beta-/- mice. These effects are associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNA-seq analysis of human HCCs identified malignant hepatocytes as the source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in both human and rodent MASH-HCCs and significantly reduced by hOSMR beta deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production, and prevented TIME markers expression by co-cultured macrophage-derived THP-1 cells.Conclusions:Our findings provide compelling evidence for an autocrine role of the OSM/OSMR beta axis in promoting CCL15 production by tumor cells, which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.
The role of OSM/OSMRβ axis in shaping the tumor microenvironment favoring MASLD-related HCC immune evasion
Kowalik M. A.;Caddeo A.;Gaia S.;Perra A.;Altucci L.;Albano E.;
2026-01-01
Abstract
Background and Aims:Oncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here, we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs.Approach and Results:OSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild-type and hepatocyte-specific OSM receptor-beta (hOSMR beta-/-) deficient mice, and in vitro experiments performed on liver cancer and immune cell lines. Analysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMR beta-/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMR beta-/- mice. These effects are associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNA-seq analysis of human HCCs identified malignant hepatocytes as the source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in both human and rodent MASH-HCCs and significantly reduced by hOSMR beta deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production, and prevented TIME markers expression by co-cultured macrophage-derived THP-1 cells.Conclusions:Our findings provide compelling evidence for an autocrine role of the OSM/OSMR beta axis in promoting CCL15 production by tumor cells, which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.
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