Lactate Secreted by PKM2 Upregulation Promotes Galectin-9-Mediated Immunosuppression via Inhibiting NF-κB Pathway in HNSCC

Abstract Background: Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis, and which plays a critical role in tumor progression in various malignancies. However, whether PKM2 can promote head and neck squamous cell carcinoma (HNSCC) progression and immunosuppression remains unknown. Methods: PKM2 expression was evaluated using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. Results: Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. Furthermore, lactate production induced by PKM2 significantly promotes migration and invasion. A positive correlation between PKM2 and galectin-9 expression is observed in HNSCC tissues. Finally, the induction of galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor.Conclusion: Our findings demonstrate that PKM2 promotes tumor progression and galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-galectin-9 axis might be a potential therapeutic target in HNSCC.