〔Abstract〕 Objective To investigate DERL1 protein expression in esophageal squamous cell carcinoma (ESCC) and its impact on prognosis, malignant behavior, and the immune microenvironment. Methods DERL1 expression in ESCC and adjacent tissues was detected by immunohistochemistry to analyze its clinicopathological and prognostic significance. After DERL1 knockdown in human esophageal cancer cell lines TE-1 and KYSE-450 cells, cell proliferation, colony formation, and migration were assessed via CCK-8, plate colony, and Transwell assays. The correlation between DERL1 and immune infiltration was analyzed using TIMER2.0 and validated by multiplex immunofluorescence. Results DERL1 protein was significantly upregulated in ESCC tissues. High DERL1 expression predicted shorter overall survival (Log-rank P=0.011) and served as an independent prognostic risk factor (HR=8.717, P=0.035). Functional cellular assays showed that DERL1 knockdown significantly inhibited proliferation, colony formation, and migration/invasion in both TE-1 and KYSE-450 cells (P<0.05). Bioinformatics analysis revealed that DERL1 expression was positively correlated with M0 macrophages and resting CD4+ memory T cells, while negatively correlated with CD8+T cells. Multiplex immunofluorescence indicated that regions with high DERL1 expression exhibited increased CD4+ but decreased CD8+ T cell infiltration. Conclusion DERL1 protein is highly expressed in ESCC and serves as an independent biomarker of poor prognosis. DERL1 promotes tumor cell proliferation and migration and is associated with an immunosuppressive tumor microenvironment. These findings suggest that DERL1 may serve as a potential therapeutic target for esophageal squamous cell carcinoma.