A Nanounit Strategy Disrupts Energy Metabolism and Alleviates Immunosuppression for Cancer Therapy

• DOI: 10.1021/acs.nanolett.2c02475
• Publication Date: 2022-07-20T13:27:20Z
• Authors: Yang Luo; Yingmin Li; Zhengjie Huang; Xinyang Li; Yi Wang; Jianwen Hou; Shaobing Zhou
• Keywords: Immunosuppression Therapy; 0301 basic medicine; 03 medical and health sciences; Glucose; Cell Line, Tumor; Neoplasms; Lactates; Tumor Microenvironment; Humans; Energy Metabolism; Glycolysis; 3. Good health

Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.