Overall, we delineated cell–cell interaction landscape of tumor cells and immune cells and revealed that Plac1+ tumor cells recruited CD4+ T cells through the CXCL11/CXCR3 axis and then induced Treg differentiation through PVR/TIGIT to shape the immunosuppressive TME of HNSCC. This evidence concerns the gene PLAC1 and head and neck squamous cell carcinoma.