CD73 is associated with glycolysis‐related metabolic features in head and neck squamous cell carcinoma

CD73, encoded by NT5E, is an ecto-5'-nucleotidase implicated in tumour progression, but its association with glycolysis-related metabolic features in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, we combined public transcriptomic analyses with in vitro and in vivo experiments to investigate the relationship between NT5E/CD73 and these features in HNSCC. NT5E expression was positively associated with glycolysis-related signatures, and a high glycolysis score was associated with poorer overall survival in an exploratory analysis. In CAL27 cells, NT5E knockdown reduced extracellular acidification rate and oxygen consumption rate and decreased the expression of glucose transporter 3 (GLUT3), lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2), indicating a broader reduction in metabolic activity. In a xenograft model, NT5E depletion suppressed tumour growth and reduced GLUT3, LDHA and PKM2 expression. ADORA2B was upregulated in HNSCC, and its silencing decreased glycolysis-related gene expression, whereas pharmacological activation of A2B partially restored glycolysis-related protein expression and migratory capacity after NT5E knockdown. These findings support an association between NT5E/CD73 and glycolysis-related metabolic features in HNSCC and suggest that A2B signalling may contribute, at least in part, to the associated metabolic and migratory changes.