Although therapeutic experiments could not be performed in mice due to the absence of therapeutic Sema6D-blocking antibodies, our data suggest that Sema6D may be a novel therapeutic target to improve the efficacy of immunotherapies, and Sema6D expression in the TME might be a biomarker for predicting the efficacy of ICIs in diverse cancers, including HNSCC. The gene discussed is SEMA6D; the disease is head and neck squamous cell carcinoma.