Integrative Multi-Omics and Pan-Cancer Analyses Identify CCL20 as a Prognostic Biomarker with Therapeutic Relevance in Esophageal Cancer

Background: CCL20 is a key chemokine involved in tumor-associated inflammation and immune microenvironment remodeling, but its biological and clinical relevance in esophageal cancer (ESCA) and across cancers remains incompletely defined. This study aimed to systematically characterize the expression pattern, prognostic value, immune associations, and potential translational relevance of CCL20 using an integrative multi-omics framework. Methods: The biological and clinical significance of CCL20 was investigated through differential expression analysis, weighted gene co-expression network analysis, survival and clinicopathological association analyses, ROC-based diagnostic evaluation, immune infiltration and tumor microenvironment characterization, immune checkpoint correlation analysis, single-cell transcriptomic analysis, in silico knockout analysis, drug sensitivity prediction, molecular docking, and tissue microarray-based immunohistochemistry. Results: CCL20 was aberrantly upregulated in ESCA and multiple other solid tumors, and its high expression was associated with poor prognosis in several cancer types. Tissue microarray-based immunohistochemistry further confirmed CCL20 overexpression at the protein level in ESCA. In the TCGA cohort, CCL20 showed favorable diagnostic performance and was associated with poorer survival outcomes in ESCA. High CCL20 expression was also closely associated with immunoregulatory infiltration patterns, increased immune checkpoint expression, and enhanced stromal features. Single-cell analysis showed that CCL20 was predominantly expressed in monocytes/macrophages and may mediate immune communication between myeloid and lymphoid/dendritic cells through the CCL20–CCR6 axis. In silico knockout analysis further suggested that CCL20 depletion perturbs inflammation-, chemotaxis-, and immune regulation-related transcriptional programs in monocytes/macrophages. Drug sensitivity prediction and molecular docking provided preliminary clues supporting the therapeutic relevance of the CCL20 axis. Conclusions: CCL20 may represent a biologically relevant candidate biomarker in ESCA, with potential diagnostic, prognostic, and therapeutic relevance.