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Kdm2a histone demethylase ablation restores anti-tumor immunogenicity in liver cancer
Laura Gragnani1, Matteo Lulli2, Patrizio Caini3
1Department of Translational Research and New Medical and Surgical Technologies, University of Pisa, Pisa, Italy. laura.gragnani@unipi.it.
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.
Insights
Targeting KDM2A, a key epigenetic regulator, enhances liver cancer immunogenicity by improving mitochondrial function and T-cell infiltration. This approach may boost responses to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Liver cancer poses a global health challenge with poor responses to immunotherapy due to immune evasion.
- Chromatin modifiers influence tumor immunogenicity, but their specific roles in liver cancer immunity require further elucidation.
Purpose of the Study:
- To investigate the role of the histone demethylase KDM2A in liver cancer immunity.
- To assess the impact of KDM2A on mitochondrial function, genomic stability, and the tumor immune microenvironment.
Main Methods:
- Genetic silencing of KDM2A in vitro and in vivo.
- Transcriptomic, epigenomic, and immune infiltration analyses in human tumors and mouse models.
- Evaluation of mitochondrial function, redox balance, and genomic stability.
Main Results:
- KDM2A silencing activated immune pathways by inducing mitochondrial dysfunction, redox imbalance, and DNA damage.
- KDM2A loss altered H3K36me2 deposition, impacting chemokine signaling and T-cell recruitment.
- High KDM2A expression correlated with immune exclusion in human liver tumors, while KDM2A loss increased CD8+ T-cell infiltration in mouse models.
Conclusions:
- KDM2A is a critical epigenetic regulator of liver cancer immunity, influencing mitochondrial function and genomic stability.
- Targeting KDM2A presents a potential strategy to enhance tumor immunogenicity and improve immunotherapy outcomes.
