TNFRSF4 (also known as CD134/OX40) is one of the representative targets of second-generation immune checkpoints, and its clinical efficacy has been observed by anti-TNFRSF4 (MEDI6469) therapy in HNSCC patients through regulating antigen-specific tumor-infiltrating T cells (Duhen et al., 2021). Here, TNFRSF4 is linked to head and neck squamous cell carcinoma.