The role of OSM/OSMRβ axis in shaping the tumor microenvironment favoring MASLD-related HCC immune evasion

Jessica Nurcis; Beatrice Foglia; Chiara Rosso; Alessia Provera; Cristina Vecchio; Marina Maggiora; Alessandro Gambella; Ugo Chianese; Claudia Bocca; Gian Paolo Caviglia; Rosaria Benedetti; Erica Novo; Francesca Bossi; Francesca Doto; Marta Anna Kowalik; Andrea Caddeo; Patrizia Carucci; Silvia Gaia; Renato Romagnoli; Alessio Menconi; Ignazia Tusa; Elisabetta Rovida; Andrea Perra; Elisabetta Bugianesi; Lucia Altucci; Emanuele Albano; Maurizio Parola; Salvatore Sutti; Stefania Cannito

doi:10.1097/HEP.0000000000001733

The role of OSM/OSMRβ axis in shaping the tumor microenvironment favoring MASLD-related HCC immune evasion

Hepatology. 2026 Mar 4. doi: 10.1097/HEP.0000000000001733. Online ahead of print.

Authors

Jessica Nurcis¹, Beatrice Foglia¹, Chiara Rosso^{2

3}, Alessia Provera⁴, Cristina Vecchio⁴, Marina Maggiora¹, Alessandro Gambella⁵, Ugo Chianese⁶, Claudia Bocca¹, Gian Paolo Caviglia^{2

3}, Rosaria Benedetti^{6

7}, Erica Novo¹, Francesca Bossi¹, Francesca Doto¹, Marta Anna Kowalik⁸, Andrea Caddeo⁸, Patrizia Carucci², Silvia Gaia², Renato Romagnoli⁹, Alessio Menconi¹⁰, Ignazia Tusa¹⁰, Elisabetta Rovida¹⁰, Andrea Perra⁸, Elisabetta Bugianesi^{2

3}, Lucia Altucci^{6

11}, Emanuele Albano⁴, Maurizio Parola¹, Salvatore Sutti⁴, Stefania Cannito¹

Affiliations

¹ Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Turin, Turin, Italy.
² Division of Gastroenterology, Città della Salute e della Scienza University Hospital, Turin, Italy.
³ Department of Medical Sciences, University of Turin, Turin, Italy.
⁴ Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University of East Piedmont "Amedeo Avogadro," Novara, Italy.
⁵ Department of Surgical Sciences and Integrated Diagnostics (DISC), Pathology Unit, University of Genoa, Genoa, Italy.
⁶ Department of Precision Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy.
⁷ Program of Medical Epigenetics, Vanvitelli Hospital, Naples, Italy.
⁸ Department of Biomedical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy.
⁹ Division of General Surgery 2U, Liver Transplant Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
¹⁰ Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy.
¹¹ Biogem Institute of Molecular and Genetic Biology, Ariano Irpino, Italy.

PMID: 41779954
DOI: 10.1097/HEP.0000000000001733

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-β (hOSMRβ -/- ) 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. hOSMRβ -/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMRβ -/- 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 hOSMRβ 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/OSMRβ 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.

Keywords: metabolic dysfunction–associated steatohepatitis (MASH)–related hepatocellular carcinoma; oncostatin M; tumor immunosuppressive microenvironment (TIME); tumor-associated macrophages (TAMs); tumor–stroma interaction.