Background Increasing evidence has shown that N6-methyladenosine (m6A) RNA methylation regulators have important biological functions in human cancers. However, there are few studies on the value of m6A reader protein YTHDC2 in the diagnosis and tumor-infiltrating of head and neck squamous cell carcinoma (HNSCC). Therefore, it is important to understand the potential clinical value of YTHDC2 in the prognosis and immune infiltration of HNSCC. Methods In this study, gene expression profiles and the corresponding clinical information of 270 HNSCC patients were downloaded from the Gene Expression Omnibus (GEO) database. The gene co-expression network was established to verify whether YTHDC2 was related to the prognosis of HNSCC and verified again in the public database. The correlations between YTHDC2 and immune infiltration was investigated via Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). Results The results showed that YTHDC2 appeared in the blue module related to survival time and survival state and had a close correlation with the prognosis and immune infiltration level of HNSCC in public database. Patients with low expression of YTHDC2 had poor overall survival (OS) and recurrence-free survival (RFS) than those with high expression. In addition, the expression of YTHDC2 was positively correlated with the level of CD4+ T cell subpopulations infiltration in HNSCC. Conclusions Through this study, we found that YTHDC2 is a tumor suppressor gene with high expression in normal tissues and low expression in tumor tissues. In addition, YTHDC2 is correlated with the immune infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells in HNSCC, which may become a potential marker for prognosis and immune infiltration of HNSCC.

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