Kdm2a histone demethylase ablation restores anti-tumor immunogenicity in liver cancer
9 affiliations
- 1Department of Translational Research and New Medical and Surgical Technologies, University of Pisa, Pisa, Italy
- 2Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- 3Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- 4Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
- 5Department of Life Sciences, Health and Health Professions Link Campus University, Rome, Italy
- 6Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- 7The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
- 8Department of Cellular Pathology, Royal Free Hospital, London, UK
- 9University College London (UCL), Institute for Liver & Digestive Health, London, UK
Abstract
Background: Liver cancer remains a major global challenge, with limited benefit from immune checkpoint inhibitors due to strong immune evasion. Emerging evidence indicates that chromatin modifiers shape tumor immunogenicity, but their roles in liver cancer immunity are not fully understood.
Methods: We investigated the role of the histone demethylase KDM2A in liver cancer using genetic silencing in vitro and in vivo. We evaluated mitochondrial function, redox balance, genomic stability, and performed transcriptomic and epigenomic analyses to assess immune pathway changes and H3K36me2 distribution. Immune infiltration was analyzed in human liver tumors and syngeneic mouse models.
Results: KDM2A silencing caused mitochondrial dysfunction, redox imbalance, and DNA damage, leading to activation of innate and adaptive immune pathways. It also reshaped H3K36me2 deposition at loci regulating chemokine signaling, metabolism, and T-cell recruitment. In human liver tumors, high KDM2A expression correlated with poor differentiation, macrophage enrichment, and exclusion of CD8⁺ T cells, consistent with an immune-excluded phenotype. In syngeneic models, KDM2A loss increased intratumoral CD8⁺ T-cell infiltration.
Conclusions: KDM2A acts as a key epigenetic regulator of mitochondrial function, genomic stability, and the tumor immune microenvironment in liver cancer. Targeting KDM2A may enhance tumor immunogenicity and improve responses to immunotherapy, representing a promising therapeutic strategy.
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BibTeX
@article{gragnani2026kdm2a,
title = {{Kdm2a histone demethylase ablation restores anti-tumor immunogenicity in liver cancer}},
author = {Laura Gragnani and Matteo Lulli and Patrizio Caini and Pinuccia Faviana and Rossella Del Frate and Enrico Desideri and Katia De Ieso and Francesco Bartoli and Andrew Hall and Tu Vinh Luong and Krista Rombouts and Vinicio Carloni},
journal = {British Journal of Cancer},
year = {2026},
month = aug,
doi = {10.1038/s41416-026-03566-z},
url = {https://doi.org/10.1038/s41416-026-03566-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Kdm2a histone demethylase ablation restores anti-tumor immunogenicity in liver cancer
AU - Laura Gragnani
AU - Matteo Lulli
AU - Patrizio Caini
AU - Pinuccia Faviana
AU - Rossella Del Frate
AU - Enrico Desideri
AU - Katia De Ieso
AU - Francesco Bartoli
AU - Andrew Hall
AU - Tu Vinh Luong
AU - Krista Rombouts
AU - Vinicio Carloni
PY - 2026
DA - 2026/08/19
JO - British Journal of Cancer
DO - 10.1038/s41416-026-03566-z
UR - https://doi.org/10.1038/s41416-026-03566-z
AB - Background: Liver cancer remains a major global challenge, with limited benefit from immune checkpoint inhibitors due to strong immune evasion. Emerging evidence indicates that chromatin modifiers shape tumor immunogenicity, but their roles in liver cancer immunity are not fully understood. Methods: We investigated the role of the histone demethylase KDM2A in liver cancer using genetic silencing in vitro and in vivo. We evaluated mitochondrial function, redox balance, genomic stability, and performed transcriptomic and epigenomic analyses to assess immune pathway changes and H3K36me2 distribution. Immune infiltration was analyzed in human liver tumors and syngeneic mouse models. Results: KDM2A silencing caused mitochondrial dysfunction, redox imbalance, and DNA damage, leading to activation of innate and adaptive immune pathways. It also reshaped H3K36me2 deposition at loci regulating chemokine signaling, metabolism, and T-cell recruitment. In human liver tumors, high KDM2A expression correlated with poor differentiation, macrophage enrichment, and exclusion of CD8⁺ T cells, consistent with an immune-excluded phenotype. In syngeneic models, KDM2A loss increased intratumoral CD8⁺ T-cell infiltration. Conclusions: KDM2A acts as a key epigenetic regulator of mitochondrial function, genomic stability, and the tumor immune microenvironment in liver cancer. Targeting KDM2A may enhance tumor immunogenicity and improve responses to immunotherapy, representing a promising therapeutic strategy.
SN - 0007-0920
SN - 1532-1827
ER -