Pan-Cancer Multi-Omics Analysis Uncovers CHD4 Driving Tumor Progression via Epigenetic Regulation of Genomic Stability and the Immune Microenvironment

Background Chromodomain Helicase DNA-Binding Protein 4 (CHD4), the core ATPase subunit of the NuRD complex, plays a critical role in epigenetic regulation. However, its systematic function across pan-cancer contexts and the synergistic regulatory mechanisms governing genomic stability and the immune microenvironment remain poorly characterized. Methods This study analyzed the expression patterns, clinical prognostic value, and genomic alteration profiles of CHD4 across pan-cancer based on multi-omics data. Associations with genomic instability, the tumor immune microenvironment, and therapeutic responsiveness were investigated. Functional enrichment, drug sensitivity screening, and in vitro experiments were conducted to validate its molecular mechanisms. Results CHD4 was significantly upregulated in multiple cancer types, and its elevated expression was strongly associated with poor patient prognosis. Integrated analysis revealed that CHD4 expression correlated strongly with markers of genomic instability, including homologous recombination deficiency (HRD) and loss of heterozygosity (LOH), and was concurrently associated with an immunosuppressive microenvironment, characterized by decreased CD8 + T cell infiltration and increased expression of immune checkpoint molecules. Mechanistically, CHD4 expression was closely associated with components of the NuRD complex, including HDAC1 and HDAC2, and facilitated histone deacetylation, which altered chromatin accessibility and thereby promoted immune evasion and genomic instability. Furthermore, drug sensitivity analyses revealed that tumors with high CHD4 expression exhibited significant sensitivity to histone deacetylase (HDAC) inhibitors, such as vorinostat and panobinostat. Conclusion This study reveals that CHD4 functions as a master epigenetic orchestrator that promotes tumor progression by concurrently inducing genomic instability and fostering an immunosuppressive microenvironment. Furthermore, the predictive value of CHD4 for sensitivity to HDAC inhibitors offers a novel strategy for epigenetics-guided precision therapy.