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Aim <p>This study aims to explore the dynamic tumor microenvironment of hepatocellular carcinoma (HCC) through deep transcriptomic analysis and to identify key regulatory genes, among which MRE11 was further validated for its immunomodulatory and prognostic significance.</p> Methods <p>We performed Summary-data-based Mendelian Randomization (SMR) analysis to identify genes causally associated with HCC and intersected these with DNA damage repair (DDR) genes, leading to the identification of MRE11. A comprehensive evaluation of MRE11 expression in HCC was conducted using transcriptomic data analysis. We collected data from 92 HCC patient samples and validated MRE11 expression differences in HCC tissues through qPCR, immunohistochemistry, and Western blotting. Publicly available single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics were utilized to explore MRE11’s dynamic mechanisms in the tumor microenvironment (TME) of both primary and post-immunotherapy cases. We also screened for differentially expressed genes and constructed a robust HCC prognosis model using 101 machine-learning algorithms.</p> Results <p>Our results demonstrated that high MRE11 expression is strongly associated with poor prognosis in HCC. In the primary TME, MRE11 regulates immune responses, facilitating immune evasion. Single-cell analysis revealed significant tumor heterogeneity in MRE11 high-expression groups, particularly in macrophages and malignant cells, where MRE11 regulates immune evasion and tumor progression via the cGAS-STING pathway and HGF-MET axis. Under immunotherapy, high MRE11 expression facilitated epithelial-mesenchymal transition (EMT) and extensive remodeling of the TME. Furthermore, MRE11 dynamically enhanced macrophage regulation, exhibiting immunosuppressive and tumor-invasive features. Finally, our prognostic model exhibited strong predictive accuracy across multiple datasets.</p> Conclusion <p>High MRE11 expression is crucial in regulating the immune microenvironment in HCC, fostering immune evasion and driving tumor progression. MRE11 emerges as a promising biomarker for HCC diagnosis and a potential target for personalized immunotherapy.</p>

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Elucidating the dynamic tumor microenvironment through deep transcriptomic analysis and therapeutic implication of MRE11 expression patterns in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月21日

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  • Ruiqiu Chen,
  • Chaohui Xiao,
  • Zizheng Wang,
  • Guineng Zeng,
  • Shaoming Song,
  • Gong Zhang,
  • Lin Zhu,
  • Penghui Yang,
  • Rong Liu

摘要

Aim

This study aims to explore the dynamic tumor microenvironment of hepatocellular carcinoma (HCC) through deep transcriptomic analysis and to identify key regulatory genes, among which MRE11 was further validated for its immunomodulatory and prognostic significance.

Methods

We performed Summary-data-based Mendelian Randomization (SMR) analysis to identify genes causally associated with HCC and intersected these with DNA damage repair (DDR) genes, leading to the identification of MRE11. A comprehensive evaluation of MRE11 expression in HCC was conducted using transcriptomic data analysis. We collected data from 92 HCC patient samples and validated MRE11 expression differences in HCC tissues through qPCR, immunohistochemistry, and Western blotting. Publicly available single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics were utilized to explore MRE11’s dynamic mechanisms in the tumor microenvironment (TME) of both primary and post-immunotherapy cases. We also screened for differentially expressed genes and constructed a robust HCC prognosis model using 101 machine-learning algorithms.

Results

Our results demonstrated that high MRE11 expression is strongly associated with poor prognosis in HCC. In the primary TME, MRE11 regulates immune responses, facilitating immune evasion. Single-cell analysis revealed significant tumor heterogeneity in MRE11 high-expression groups, particularly in macrophages and malignant cells, where MRE11 regulates immune evasion and tumor progression via the cGAS-STING pathway and HGF-MET axis. Under immunotherapy, high MRE11 expression facilitated epithelial-mesenchymal transition (EMT) and extensive remodeling of the TME. Furthermore, MRE11 dynamically enhanced macrophage regulation, exhibiting immunosuppressive and tumor-invasive features. Finally, our prognostic model exhibited strong predictive accuracy across multiple datasets.

Conclusion

High MRE11 expression is crucial in regulating the immune microenvironment in HCC, fostering immune evasion and driving tumor progression. MRE11 emerges as a promising biomarker for HCC diagnosis and a potential target for personalized immunotherapy.