Background: Tongue squamous cell carcinoma (TSCC) is characterized by aggressive invasion and poor prognosis. Currently, immune checkpoint inhibitors may prolong overall survival compared with conventional treatments. However, PD1/PDL1 remain inapplicable in predicting the prognosis of TSCC; thus, it is urgent to explore the genetic characteristics of TSCC.Materials and methods: We utilized single‐sample gene set enrichment analysis (ssGSEA) to classify TSCC patients from the TCGA database into clusters with different immune cell infiltrations. ESTIMATE (immune‐related scores) and CIBERSORT (immune cell distribution) analyses were used to evaluate the immune landscape among clusters. GO, KEGG, and GSEA analyses were performed to analyze the different underlying molecular mechanisms in the clusters. Based on the immune characteristics, we applied the LASSO Cox regression to select hub genes and construct a prognostic risk model. Finally, we established an interactive network among these hub genes by using Cytoscape, and a pan‐cancer analysis to further verify and decipher the innate function of these genes.Results: Using ssGSEA, we constructed three functional clusters with different overall survival and immune‐cell infiltration. ESTIMATE and CIBERSORT analyses revealed the different distributions of immune cells (T cells, B cells, and macrophages) with diverse immune‐related scores (ESTIMATE, immune, stromal, and tumor purity scores). Moreover, pathways including those of the interferon‐gamma response, hypoxia, and glycolysis of the different subtypes were investigated to elucidate their involvement in mediating the heterogeneous immune characteristics. Subsequently, after LASSO Cox regression, a signature of 15 immune‐related genes was established that is more prognostically effective than the TNM stage. Furthermore, three hub genes—PGK1, GPI, and RPE—were selected using Cytoscape evaluation and verified by immunohistochemistry. PGK1, the foremost regulator, was a comprehensively profiled pan‐cancer, and a PGK1‐based interactive network was established.Conclusion: Our results suggest that immune‐related genes and clusters in TSCC have the potential to guide individualized treatments.