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

Abstract

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.

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

“…Further studies have revealed that the tumor growth rate positively correlates with glucose levels and that high glucose levels in cancer patients are associated with poor prognosis [ 7 , 8 , 9 ]. Thus, cancer starvation therapy based on glucose deprivation is emerging as an effective treatment for suppressing tumor growth [ 10 , 11 , 12 ]. For example, the ketogenic diet can inhibit the metabolic proliferation of cancer cells by reducing blood glucose [ 13 , 14 , 15 ].…”

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

“…Hexokinase 2-DG is an effective HK inhibitor to repress the Warburg effect phenotype of cancers (Pouysségur et al, 2022). Luo et al (2022) designed a novel multi-targeted nano drug termed D/B/ CQ@ZIF-8@CS enveloping 2-DG, BAY-876 (GLUT1 inhibitor), and chloroquine (CQ), which sufficiently inhibits the aerobic glycolysis procedure of cancer cells. Significantly, the drug synthetically improves the anti-CTLA-4 immunotherapy efficacy by reducing Tregs metabolic fitness in the relieved TME, which is used to be glucose-deficient and lactateenriched (Luo et al, 2022).…”

“… Luo et al (2022) designed a novel multi-targeted nano drug termed D/B/CQ@ZIF-8@CS enveloping 2-DG, BAY-876 (GLUT1 inhibitor), and chloroquine (CQ), which sufficiently inhibits the aerobic glycolysis procedure of cancer cells. Significantly, the drug synthetically improves the anti-CTLA-4 immunotherapy efficacy by reducing Tregs metabolic fitness in the relieved TME, which is used to be glucose-deficient and lactate-enriched ( Luo et al, 2022 ). In ovarian cancer, Tregs pretreated with 2-DG also alleviate the inhibition of effector T cell proliferation ( Xu et al, 2021b ).…”

Multifunctional Liposomes Remodeling Tumor Immune Microenvironment for Tumor Chemoimmunotherapy

“…[1] In recent years, T-cell-based immunotherapy, such as immune checkpoint inhibitors, therapeutic tumor vaccines, and chimeric antigen receptor (CAR) T-cell therapies, has become a rising strategy for promoting systemic immune detection and eliminating primary tumors, as well as metastatic tumors. [2][3][4][5] Despite T cells based immunotherapy having been shown to be effective in some DOI: 10.1002/smtd.202201327 patients and providing consistent clearance of tumor cells in advanced metastatic tumors, the efficiency is still limited due to the low responsiveness and insufficient infiltration of T cells. [6] Therefore, it is highly reasonable to improve the response and infiltration of T cells by converting "cold tumors" (tumors with weak tumor immunogenicity) into "hot tumors" (tumors with strong immunogenicity).…”