BACKGROUND: Our previous study demonstrated that CCL26 secreted by cancer-associated fibroblasts (CAF) promoted the invasive phenotype of oral squamous cell carcinoma (OSCC), however, more comprehensive clinical expression patterns of CCL26 and its role in immunotherapy remains ambiguous. METHODS: CCL26 levels in different cancer and normal tissues were analyzed and validated in 67 OSCC patients through immunohistochemical staining (IHC). The clinical spatial distribution pattern of CCL26 in tumor microenvironment was determined, and its clinical outcomes were investigated. We also determined the invasive phenotype of tumor cells with distinct CCL26 level and explored its immune checkpoint and immunocytes relevance by differentially expressed gene (DEG) analysis, GSEA, and GO analysis. We collected peripheral blood from 28 OSCC patients to assess the percentage and absolute number of lymphocytes by flow cytometry. RESULTS: CCL26 was upregulated in HNSC and preferentially high-expressed on CAFs and tumor cells in OSCC patients, which exhibits a trend toward decreased overall survival. CCL26 CONCLUSION: CCL26 could regulate Immune balance and promote invasiveness of OSCC, which gave a new insight into a potential immunotherapy strategy.