In this study, we show that PHLDB2 depletion induces effective antitumoral immunity through recruitment of cytotoxic CD8+ T cells and the remodeling of the tumor microenvironment in HNSCC, which suggests that targeting PHLDB2 may be an effective strategy to improve PD-1 immunotherapy. Here, PDCD1 is linked to head and neck squamous cell carcinoma.