Herein, the potential mechanisms underlying the crosstalk between PD-1/PD-L1 blockade and its combinatorial therapies for HNSCC were reviewed, and it is hoped that the improved understanding of the crosstalk process would provide further ideas for the design of a combinatorial regimen with a higher efficiency and response rate for the treatment of HNSCC and other malignancies. The gene discussed is PDCD1; the disease is head and neck squamous cell carcinoma.