Taken together, these findings strongly suggest that HA–CD44 interaction plays an important role in promoting Nanog/Oct4/Sox2 upregulation, stemness properties, tumorigenesis and chemoresistance in CD44v3highALDH1high head and neck CSCs, which are important contributors to HNSCC progression. This evidence concerns the gene POU5F1 and head and neck squamous cell carcinoma.