In this review, we summarized its combination with other current treatment options for HNSCC (including chemotherapy, radiotherapy, targeted therapy, and immunotherapy) from their crosstalk in the TME (Figure 1) to the ongoing clinical trials (Table 1), in order to better understand the mechanism of interaction between PD-1/PD-L1 blockade and other cancer therapies, and to provide further ideas for the design of combinatorial regimen with a higher efficiency and response rate in HNSCC and other malignancies. This evidence concerns the gene CD274 and head and neck squamous cell carcinoma.