PAN-CANCER ANALYSIS OF CHEMOKINE (C-C MOTIF) LIGAND 26 (CCL26) AS A PROMISING PROGNOSTIC BIOMARKER AND IMMUNOMODULATORY MEDIATOR.

BACKGROUND: Chemokine (C-C motif) ligand 26 (CCL26), also known as eotaxin-3, is an immune-regulatory chemokine involved in inflammatory responses and immune cell recruitment. Emerging evidence suggests its expression is dysregulated across multiple malignancies, yet comprehensive pan-cancer evaluations remain limited. OBJECTIVES: To systematically analyze CCL26 expression, clinicopathological correlations, survival associations, and immune modulatory functions across 33 cancer types, and evaluate its potential as a prognostic biomarker and immunomodulatory therapeutic target. METHODS: CCL26 expression was analyzed using GEPIA, TIMER2.0, and UALCAN, three platforms that share the TCGA data source but employ distinct analytical pipelines; cross-platform concordance was therefore used as a measure of pipeline robustness, not validation. external validation was performed using four GEO microarray cohorts (GSE53757, GSE30219, GSE39582, and GSE33479) Results: CCL26 was significantly upregulated in 11 cancer types (33.33%), particularly epithelial malignancies including lung squamous cell carcinoma (LUSC), colon adenocarcinoma (COAD), and esophageal carcinoma (ESCA), and downregulated in genitourinary cancers including kidney renal papillary cell carcinoma (KIRP) and prostate adenocarcinoma (PRAD). Cross-database validation achieved 96.97% concordance. Expression correlated with advancing cancer stage, older age (61-80 years), and racial/ethnic background. Survival analysis revealed opposing prognostic associations: high CCL26 predicted poor outcomes in LIHC, KIRC, and KIRP (HR 1.45-3.79, p<0.036), but favorable outcomes in STAD and ESCA (HR 0.35-0.71, p<0.047). Significant immune correlations were identified with dendritic cells (LUAD, r=0.373), macrophages (COAD, r=0.318), and CD4+ T cells (STAD, r=0.296). Promoter hypermethylation was identified in lung and breast cancers, with minimal genomic mutation frequency (1%). CONCLUSIONS: CCL26 exhibits cancer-type-specific expression and differential prognostic significance across malignancies. Its strong immune infiltration correlations support potential utility in prognostic panels and as an immunomodulatory target. GEO-based validation supported selected expression findings, particularly in renal and lung cohorts, while also highlighting context-dependent variability. Collectively, these data support the biological relevance of CCL26 in cancer but indicate that its clinical and therapeutic value should be interpreted in a tumor-specific manner and confirmed in further mechanistic studies.