Analysis of Aldehyde Dehydrogenase 2 as a Prognostic Marker Associated with Immune Cell infiltration and Chemotherapy Efficacy in Head and Neck Squamous Cell Carcinoma.

Previous investigations have demonstrated the role of () levels in the cancer initiation and progression, prognosis, and treatment response in kinds of malignancies. However, its significance in the head and neck squamous cell carcinoma (HNSC) by different human papillomavirus (HPV) statuses remains unclear. We conducted an in-depth analysis of in HNSC using various bioinformatics tools, investigating its expression, alteration, differential levels, prognostic significance, molecular interactions, immune characteristics, and conducting experimental validation through immunohistochemistry (IHC) arrays and Western blot to compare expression levels between tumor and normal tissues, analyze the associations with clinicopathological features, and investigate its responses to chemotherapies. levels are downregulated in HNSC tissues and associated with higher American Joint Committee on Cancer (AJCC) T classification and worse overall survival in HPV-unrelated HNSC, yet not in HPV-related HNSC. is positively regulated by copy-number variation and negatively regulated by DNA methylation. The association of with prognosis may be due to its interaction with , and its co-expressed genes are predictive biomarkers of HNSC. We also found high levels in bulk tumors are associated with increased immune surveillance cells, such as naïve B cells and M1 macrophages in HPV-unrelated HNSC. IHC and western blot showed that ALDH2 is downregulated in the oral cavity, hypopharyngeal cancers, and well-differentiated carcinoma. , low levels showed reduced response to 5-fluorouracil in HNSC-derived cell lines. Our analyses revealed the genetic and cellular targets and drug response of ALDH2 in HNSC. We also found is involved in regulating the immune response of the tumor microenvironment, and high levels of in bulk HNSC may enhance antitumor immunity, which could improve prognosis. These findings suggest that could be a potential biomarker in improving risk stratification and tailoring treatment strategies in HNSC patients, especially in the HPV-unrelated subgroup.