H4-methylation regulators mediated epitranscriptome patterns and tumor microenvironment infiltration characterization...

Area of Science:

• Oncology
• Epigenetics
• Immunology

Background:

• Epigenetic modifications are crucial for tumor microenvironment (TME) remodeling and immune response regulation.
• The specific role of histone H4 methylation (H4M) in hepatocellular carcinoma (HCC) TME and immunity remains largely unexplored.

Purpose of the Study:

• To identify H4M-mediated modification patterns in HCC.
• To investigate the impact of these patterns on TME and immunologic characteristics.
• To assess the prognostic and predictive value of H4M patterns in HCC.

Main Methods:

• Consensus clustering analysis of H4M patterns across 2305 samples from 13 cohorts.
• Development of an H4Mscore using principal component analysis.
• Correlation analysis with TME infiltration, homologous recombination deficiency (HRD), intratumor heterogeneity, proliferation, stemness, and prognosis.
• Validation in internal and external cohorts, including immunotherapy datasets.

Main Results:

• Three distinct H4M modification patterns were identified, correlating with TME infiltration, biological processes, and clinical outcomes.
• The H4Mscore effectively predicted TME infiltration, HRD, heterogeneity, proliferation, stemness, and prognosis.
• A low H4Mscore was associated with an inflamed TME, superior immunotherapy response (anti-PD-1/L1, anti-CTLA4), and improved survival.
• Prognostic value was validated across multiple cohorts.

Conclusions:

• H4M modification significantly shapes TME diversity and complexity in HCC.
• The H4Mscore serves as a valuable biomarker for predicting TME features and patient outcomes.
• Evaluating H4M patterns can inform the development of more effective HCC immunotherapy strategies.