Abstract
AIM: To investigate the prognostic significance of histone acetylation (HAc) regulators in esophageal cancer (EC) and develop a transcriptome-based HAc_score reflecting epigenetic and immunogenomic states. METHODS: Expression and mutation from EC were analyzed to identify prognostic HAc regulators via univariable Cox models. Consensus clustering defined HAc-related expression patterns. Differentially expressed genes (DEGs) among clusters were functionally enriched. A principal component-based HAc_score was constructed from prognostic DEGs and tested for associations with overall survival, tumor mutational burden (TMB), immunophenoscore (IPS), and immune cell infiltration. RESULTS: Three HAc-related expression patterns showed distinct biological and immune features. From shared DEGs, 19 prognostic genes defined two molecular subtypes and served as the basis for the HAc_score. Higher HAc_score was associated with better overall survival, particularly in early-stage disease. HAc_score correlated inversely with TMB and positively with IPS components, suggesting a transcriptionally active, immunogenic phenotype despite lower mutation burden. Combining HAc_score with TMB improved risk stratification. CONCLUSION: HAc_score quantifies HAc–linked transcriptional states in EC and reflects tumor–immune interactions. It stratifies survival risk and complements TMB, supporting its potential use as a prognostic biomarker and integrative epigenetic–immune signature. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-025-04258-5.