Our analysis of the relationship between EPHX3 and immune checkpoints revealed that low level of EPHX3 was closely associated with CD274, IL1B, IL1A, PDCD1, PDCD1LG2, and SIRPA in HNSCC, indicating that targeting EPHX3 may improve the efficacy of immunotherapy in HNSC. Here, CD274 is linked to head and neck squamous cell carcinoma.