Background: Specific biomarkers for the diagnosis, treatment, and prognostication of thyroid cancer (THCA), the most common tumor in the endocrine system, are still lacking. CYP26A1 is overexpressed in some cancers and exerts pro-tumor effects. However, its role in THCA development has not been established. Therefore, this study aims to comprehensively investigate the potential role of CYP26A1 in THCA tumorigenesis and immune infiltration, as well as its clinical prognostic value.

Methods: Data from 510 THCA patients with complete progression-free interval (PFI) and tumor staging information were obtained from the Cancer Genome Atlas. Differentially expressed genes associated with high/low CYP26A1 expression were identified and evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, gene set enrichment analysis (GSEA), protein–protein interaction network construction, and miRNA-mRNA interaction network construction. Single-sample GSEA (ssGSEA) was performed to evaluate correlations between CYP26A1 expression and immune cell infiltration. Associations between clinical pathological characteristics and the expression of CYP26A1 were analyzed. Finally, the correlations between CYP26A1 and the hub gene expression were evaluated, along with their relationships with sensitivity to chemotherapeutic drugs and small-molecule compounds.

Results: CYP26A1 expression was higher in THCA than in paired para-cancerous tissues (p < 0.001). Genes associated with high CYP26A1 expression in THCA were enriched in pathways related to the endoplasmic reticulum lumen, P53 signaling, cytokine receptor binding, and apoptosis signaling. CYP26A1 expression was positively correlated with the abundance of various immune cells (T cells, B cells, CD8 T cells, cytotoxic cells, neutrophils, and Th1 cells). High CYP26A1 expression was related to the PFI, T stage, cervical lymph node metastasis, and extra-glandular invasion (p < 0.05).

Conclusion: High CYP26A1 expression is associated with THCA development and has prognostic value, suggesting its potential as a therapeutic target.