Abstract
Esophageal cancer (EC) is a leading cause of cancer-related mortality globally, with alcohol consumption being a significant risk factor. However, the genetic and molecular mechanisms linking alcohol intake to EC remain unclear. This study utilized Mendelian randomization analysis to establish a causal relationship between alcohol consumption and EC (OR: 4.11 [95% CI 1.83-9.23]). Transcriptomic analysis identified 83 differentially expressed genes (log₂ fold change > 1, false discovery rate [FDR] < 0.05), among which DLEU2 was uniquely transcribed into a long non-coding RNA (lncRNA). Pan-cancer analysis revealed its association with the tumor immune microenvironment and cancer progression. Single-cell RNA sequencing localized DLEU2 expression predominantly to T cells, particularly exhausted subpopulations, and pseudo-temporal analysis demonstrated increased DLEU2 expression during late T cell differentiation stages, co-expressing immune suppression markers, with consistent expression patterns observed across multiple patient-derived samples. Additionally, cell communication analysis suggested that DLEU2 modulates TNF signaling through TNFRSF1A/B pathways, contributing to immune evasion and poor prognosis. These findings position DLEU2 as a pivotal regulator of the immune landscape in EC and a potential prognostic biomarker and therapeutic target.