Objectvie To explore the role of DNAJC5B in immunotherapy for esophageal cancer. MethodsThis study utilized the ESCC dataset from the TCGA database, and selected genes associated with DNAJC5B expression through Pearson correlation analysis, followed by Gene Ontology (GO) functional enrichment analysis and KEGG pathway analysis. Additionally, single-cell RNA sequencing data was used to analyze DNAJC5B expression in different T cell subgroups. The prognostic value of DNAJC5B was evaluated using Kaplan-Meier survival curves, receiver operating characteristic (ROC) curves, and Cox proportional hazards model analysis. ResultsDNAJC5B is highly expressed in advanced esophageal cancer patients, especially in males. GO and KEGG analyses revealed a significant correlation between DNAJC5B expression and immune-related processes, such as adaptive immune response and cell surface receptor signaling pathways. Single-cell analysis indicated that DNAJC5B expression is positively correlated with immune function and primarily accumulates in CD8+ T cells. Kaplan-Meier survival curves showed that the median survival time of patients with high DNAJC5B expression was 681 days, significantly lower than the 1361 days in patients with low expression. Independent prognostic analysis revealed hazard ratios of 3.577 and 4.114 for DNAJC5B, both with P-values less than 0.05. Conclusion DNAJC5B may play a significant immunomodulatory role in esophageal cancer, particularly in regulating CD8+ T cell function and tumor immune escape. These findings support the potential of DNAJC5B as a biomarker for treatment and prognosis evaluation in esophageal cancer