Regulation of Tumor Lactate Metabolism by Targeting Glycolysis and Mitochondrial OXPHOS for Tumor Metastasis Inhibition

Regulation of tumor lactate metabolism is a promising strategy for tumor metastasis inhibition but remains challenging. Herein, a new nanodrug that can regulate tumor lactate metabolism by targeting both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) was developed by loading 3-(3-pyridyl)-1-(4-pyridyl)-2-propen-1-one (3PO) in the cross-linked sodium lipoic acid vesicle (3PO@cLANa). After entering cells, cLANa dissociated into lipoic acid/dihydrolipoic acid (LA/DHLA) and released 3PO. 3PO suppressed glycolysis through inhibiting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 and LA/DHLA enhanced mitochondrial OXPHOS through inhibiting pyruvate dehydrogenase kinase 1. Since glycolysis and mitochondrial OXPHOS are two major metabolic pathways for lactate generation, 3PO@cLANa effectively regulated the production of lactate. In vivo results disclosed that 3PO@cLANa achieved a 45.9% reduction of lactate in the B16F10 melanoma tumor model and only 11 of the metastasis foci were observed in the lungs, 1.55-fold lower than that of dacarbazine (17 metastasis foci), the first-line antitumor drug of melanoma. When combined with α-PD1, the lung metastasis foci decreased further to 5. The tumor lactate metabolism-regulated nanodrug with both glycolysis and mitochondrial OXPHOS targeting holds clinical potential.