Oxamate Nanoparticles for Enhanced Tumor Immunotherapy through Blocking Glycolysis Metabolism and Inducing Pyroptosis.

Abstract

Tumor metabolic reprogramming, particularly the Warburg effect, is crucial for rapid tumor growth and immune evasion. Lactate dehydrogenase A (LDHA), a key enzyme in tumor aerobic glycolysis, is overexpressed in tumors and is considered an effective therapeutic target. Sodium oxamate (SOM) is a classic LDHA inhibitor, but its poor cell permeability, low tumor killing effect, and ineffective immune activation limit its application. Herein, SOM nanoparticles (NPs) were prepared via a thin-film hydration method for amplified cancer immunotherapy. SOM NPs are efficiently taken up by tumor cells through endocytosis, releasing NH₂COCOO^- and Na⁺ ions, which cause osmotic pressure and oxidative stress, activating pyroptosis and immunogenic cell death (ICD) to initiate the immune response. Simultaneously, NH₂COCOO^- blocks glycolysis of tumor cells, resulting in inhibiting the proliferation, migration, and invasion and alleviating immunosuppression. This work will facilitate the application of SOM in tumor therapy and provide a new paradigm for glycolytic metabolism and pyroptosis-mediated tumor treatment.