Histone methyl-transferase G9a inhibition boosts the efficacy of immune checkpoint inhibitors in experimental hepatocellular carcinoma PMID: 41923620

ADC Targets in Oncology

2026-04-10

Histone methyl-transferase G9a inhibition boosts the efficacy of immune checkpoint inhibitors in experimental hepatocellular carcinoma

Cell Rep Med. 2026 Apr 21;7(4):102717. doi: 10.1016/j.xcrm.2026.102717.

Elena Adan-Villaescusa ¹ , Borja Castello-Uribe ¹ , Iker Uriarte ² , Eva Santamaria ³ , Roberto Barbero ² , Miriam Belzunce ¹ , Amaya López-Pascual ⁴ , Maria Ujue Latasa ¹ , Jasmin Elurbide ² , Emiliana Valbuena-Goiricelaya ¹ , Agavni Mesropian ⁵ , Guillem Cano-Segarra ⁵ , Ana Hernández de Sande ⁶ , Lorenzo Nevi ⁷ , Simone Carotti ⁷ , Umberto Vespasiani-Gentilucci ⁸ , Felipe Prosper ⁹ , Antonio Pineda-Lucena ¹⁰ , Bruno Sangro ¹¹ , Josepmaria Argemi ¹² , Pedro Berraondo ¹³ , Pablo Sarobe ¹⁴ , Albert Gris-Oliver ⁵ , Roser Pinyol ⁵ , Josep M Llovet ¹⁵ , Maria Arechederra ¹⁶ , Carmen Berasain ² , Alexis Cocozaki ¹⁷ , Veronica Gibaja ¹⁷ , Matias A Avila ¹⁶ , Maite G Fernandez-Barrena ¹⁸

Affiliations

1. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
2. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
3. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; RNA Biology and Therapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
4. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
5. Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Catalonia, Spain.
6. Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.
7. Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
8. Unità di Epatologia, Università Campus Biomedico di Roma, Rome, Italy.
9. Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hemato-Oncology Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERonc, Instituto de Salud Carlos III, Madrid, Spain.
10. Molecular Therapeutics Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
11. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain.
12. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; RNA Biology and Therapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain.
13. Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; CIBERonc, Instituto de Salud Carlos III, Madrid, Spain; Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
14. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
15. Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
16. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
17. Ipsen Biopharmaceuticals, Cambridge, MA, USA.
18. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain. Electronic address: [email protected].

Abstract

Immune checkpoint inhibitors (ICIs) transform Cancer therapy, but their efficacy in hepatocellular carcinoma (HCC) remains limited due to tumor-intrinsic immune evasion. We investigate the epigenetic regulator G9a (EHMT2) as a driver of immune resistance and evaluate pharmacologic inhibition as a therapeutic strategy. G9a expression is analyzed across human HCC cohorts and correlated with transcriptomic signatures predictive of ICI response. Using human and murine HCC cell lines and immunocompetent mouse models, we assess the antitumor effects of two G9a inhibitors, CM272 and EZM8266, combined with anti-PD1 therapy. Elevated G9a expression inversely correlates with immune-related signatures of ICI responsiveness. G9a inhibition restores interferon gamma (IFN-γ) signaling, increases major histocompatibility complex (MHC) class I expression, enhances CXCL10-mediated T cell recruitment, and induces viral mimicry via derepression of endogenous retroviral elements and cytosolic double-stranded RNA (dsRNA) accumulation. In vivo, G9a inhibition synergizes with anti-PD1 therapy, suppresses tumor growth, and enhances CD8⁺ T cell infiltration. These findings support combining G9a inhibitors with immunotherapy in HCC.

Keywords

G9a; epidrugs; epigenetics; hepatocellular carcinoma; histone methylation; immune checkpoint inhibitors; immune evasion.