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Updated: Jan 9, 2026
Mass Cytometry Analysis of Systemic and Local Immune Responses in Hepatocellular Carcinoma
Published on: April 25, 2025
G9a epigenetically suppresses CXCL10 expression and inhibits anti-tumor immunity in hepatocellular carcinoma
Xinxin Chai1,2,3, Jingzhou Chen1,2,3, Yuanyuan Zhao4,5
1Institute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
The immunosuppressive tumor microenvironment, characterized by limited immune cell infiltration, represents a major challenge for effective immunotherapy in hepatocellular carcinoma (HCC). Epigenetic dysregulation has emerged as a critical mechanism underlying tumorigenesis and progression; however, the specific epigenetic mechanisms governing immune infiltration remain poorly understood. Here, we investigated the role of G9a, a histone methyltransferase catalyzing H3K9 methylation, in modulating anti-tumor immunity in HCC. Bioinformatic analysis of human HCC datasets revealed a significant inverse correlation between G9a expression and T cell infiltration. Genetic ablation of G9a in hepatoma cells markedly enhanced CD8+ T cell recruitment and activation in immunocompetent mouse models. Through RNA sequencing and functional validation, we identified CXCL10 as the key chemokine directly repressed by G9a. Mechanistically, G9a mediates H3K9 dimethylation at the CXCL10 promoter, and G9a deletion or inhibition significantly reduced this repressive mark, resulting in increased CXCL10 expression and secretion. Importantly, neutralization of CXCL10 abolished G9a inhibition-induced enhancement of CD8+ T cell migration. In preclinical models, pharmacological inhibition of G9a with UNC0642 not only suppressed tumor growth by promoting T cell infiltration but also synergized with anti-PD1 therapy to achieve superior therapeutic efficacy. These findings establish G9a as an epigenetic regulator of anti-tumor immunity in HCC and provide evidence for combining G9a inhibitors with immune checkpoint blockade to improve outcomes for HCC patients who are receiving immunotherapy.
Insights
G9a epigenetic regulation suppresses anti-tumor immunity in hepatocellular carcinoma (HCC) by inhibiting CXCL10 chemokine. Inhibiting G9a enhances T cell infiltration and synergizes with immunotherapy, offering new treatment strategies for HCC.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Hepatocellular carcinoma (HCC) exhibits an immunosuppressive tumor microenvironment, hindering immunotherapy effectiveness.
- Epigenetic dysregulation is implicated in HCC tumorigenesis, but its role in immune infiltration is unclear.
- G9a, a histone methyltransferase, catalyzes H3K9 methylation and its role in HCC immunity requires investigation.
Purpose of the Study:
- To investigate the role of G9a in modulating anti-tumor immunity within the HCC microenvironment.
- To identify the specific epigenetic mechanisms by which G9a influences immune cell infiltration in HCC.
- To evaluate the therapeutic potential of G9a inhibition in combination with immunotherapy for HCC.
Main Methods:
- Bioinformatic analysis of human HCC datasets to correlate G9a expression with T cell infiltration.
- Genetic ablation of G9a in hepatoma cells and assessment of CD8+ T cell responses in mouse models.
- RNA sequencing to identify G9a-regulated genes, focusing on chemokines like CXCL10.
- Pharmacological inhibition of G9a using UNC0642 and evaluation of tumor growth and immune response.
Main Results:
- G9a expression inversely correlated with T cell infiltration in human HCC.
- G9a ablation enhanced CD8+ T cell recruitment and activation.
- CXCL10 was identified as a key chemokine directly repressed by G9a via H3K9 dimethylation at its promoter.
- G9a inhibition increased CXCL10 expression, promoting CD8+ T cell migration.
- Pharmacological G9a inhibition suppressed tumor growth, increased T cell infiltration, and synergized with anti-PD1 therapy.
Conclusions:
- G9a acts as an epigenetic repressor of anti-tumor immunity in HCC by downregulating CXCL10.
- G9a inhibition promotes T cell infiltration and enhances the efficacy of immunotherapy in preclinical HCC models.
- Combining G9a inhibitors with immune checkpoint blockade presents a promising therapeutic strategy for HCC patients.
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