Our data indicate a distinctive shift in soluble immune checkpoint molecules in HNSCC, most notably the significant increase in sCD27 and a decrease in sPD-L1, with other mediators (sCD25, sTIM-3, Galectin-9, sPD-1, sPD-L2, sLAG-3) remaining relatively unchanged. This evidence concerns the gene SPDL1 and head and neck squamous cell carcinoma.