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. The gene discussed is NANOG; the disease is head and neck squamous cell carcinoma.