Background: N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C) and N1-methyladenosine (m¹A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether m⁶A/m⁵C/m¹A-related long non-coding RNAs (lncRNAs) affect the prognosis of head and neck squamous cell carcinoma (HNSCC). Methods: We summarized 52 m⁶A/m⁵C/m¹A-related genes, downloaded 44 normal samples and 501 HNSCC tumor samples with RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database, and then searched for m⁶A/m⁵C/m¹A-related genes co-expressed lncRNAs. We adopt the least absolute shrinkage and selection operator (LASSO) Cox regression to obtain m⁶A/m⁵C/m¹A-related lncRNAs to construct a prognostic signature of HNSCC. Results: This prognostic signature is based on six m⁶A/m⁵C/m¹A-related lncRNAs (AL035587.1, AC009121.3, AF131215.5, FMR1-IT1, AC106820.5, PTOV1-AS2). It was found that the high-risk subgroup has worse overall survival (OS) than the low-risk subgroup. Moreover, the results showed that most immune checkpoint genes were significantly different between the two risk groups (p < 0.05). Immunity microenvironment analysis showed that the contents of NK cell resting, macrophages M2, and neutrophils in samples of low-risk group were significantly lower than those of high-risk group (p < 0.05), while the contents of B cells navie, plasma cells, and T cells regulatory (Tregs) were on the contrary (p < 0.05). In addition, patients with high tumor mutational burden (TMB) had the worse overall survival than those with low tumor mutational burden. Conclusion: Our study elucidated how m⁶A/m⁵C/m¹A-related lncRNAs are related to the prognosis, immune microenvironment, and TMB of HNSCC. In the future, these m⁶A/m⁵C/m¹A-related lncRNAs may become a new choice for immunotherapy of HNSCC.

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