Diverse patterns of transcriptional regulation and epigenetic reprogramming within PMDs contribute to ESCC progression by regulating EMT and immunosuppression.

Partially methylated domains (PMDs) represent extensive genome-wide hypomethylated regions that drive genomic instability and proto-oncogene activation. However, their complex regulatory influence on tumor-specific transcriptional networks remains largely elusive. In this study, we developed a robust computational pipeline to characterize aberrant PMD landscapes across pan-cancer. We specifically focused on the epigenetic features associated with transcriptional dysregulation in esophageal squamous cell carcinoma (ESCC). By analyzing gene expression patterns, we classified PMDs into four distinct classes and revealed that several immunosuppressive genes were recurrently activated within Tumor-PMDs across various cancers. While these PMDs were generally marked by elevated repressive H3K27me3 and diminished active histone modifications, the activated genes within them paradoxically exhibited a precise, localized enrichment of H3K9ac and H3K27ac near their transcription start sites (TSSs). This localized epigenetic rewiring suggests a potential correlation where collaborative histone modification landscapes may shape oncogenic chromatin remodeling to license transcriptional dysregulation. Furthermore, we identified a robust co-expression axis between the prognostic gene ATP6V0D2 and established immune checkpoints (HAVCR2, TDO2). Elevated ATP6V0D2 expression was found to potentially contribute to ESCC progression and poor prognosis by activating the complement system and epithelial-mesenchymal transition (EMT) pathways. Capitalizing on these findings, virtual screening and in vitro validation suggested that caffeic acid could act as a potential ATP6V0D2-binding compound, effectively suppressing the migration and viability of ESCC cells. This study further nominates caffeic acid as a candidate compound for further mechanistic and therapeutic investigation in ESCC.