Glucose and Lactate Cooperatively Deprived by a PD-1-Presenting Nanoemulsion for Potentiated Antitumor Immunotherapy.

Abstract

Immune checkpoint blockade (ICB) often fails against immunologically "cold" tumors, a challenge exacerbated by their reprogrammed metabolism. The Warburg effect drives tumor cells to rely on aerobic glycolysis, resulting in excessive lactate production. While simultaneous deprivation of glucose and lactate using glucose oxidase (GOx) and lactate oxidase (LOx) holds promise for starving tumors and alleviating immunosuppression, the activity of both enzymes is greatly constrained by tumor hypoxia. To overcome this, we develop a biomimetic nanoemulsion (FGL@PM) coloaded with GOx, LOx, and perfluorotripropylamine (FTPA), and coated with a programmed cell death 1 (PD-1)-presenting cell membrane. FTPA, owing to its high affinity for oxygen, can carry and deliver a large amount of oxygen for supporting the catalytic reactions of both GOx and LOx. This nanoemulsion enhances ICB via glucose and lactate cooperative deprivation (GLCD) strategy. In detail, surface PD-1 proteins not only blocked PD-ligand 1 (PD-L1) on tumor cells but also promoted the cellular uptake of FGL@PM. GOx catalyzed glucose oxidation, generating H₂O₂ and suppressing glycolysis and lactate production, while LOx further depletes lactate and boosted H₂O₂ generation. The resulting H₂O₂ disrupts the redox homeostasis in tumor cells and stimulates antitumor immunity. This GLCD strategy effectively suppressed tumor growth on both unilateral and bilateral subcutaneous 4T1 breast tumor models by simultaneously impairing glycolysis and oxidative phosphorylation, enhancing antigen presentation, and promoting the infiltration of antitumor T cells. This study highlights the potent combination of glucose/lactate metabolic intervention with immunotherapy for improved antitumor treatment.