| Cancer is one of the most common and malignant disease in human beings.The main treatment methods include radiotherapy,chemotherapy and surgery,but lack of effective therapy.The incidence of cancer is rapidly increasing with severe socioeconomic impacts.Immunotherapies such as checkpoint therapy,CAR-T cell therapy and TCR-T cell therapy have achieved landmark success,but these therapies are only effective in some patients.So,new therapies are demanded for cancer therapy.We will focus on the regulation of cancer cell metabolism,immunotherapy,chemotherapy and the application of nanotechnology in cancer therapy,in order to provide new targets or new ideas for cancer therapy.Highly proliferative cells increase glucose uptake and undergo upregulated aerobicglycolysis,a critical metabolic pathway for activated T cells cancer cells.Under a suppressive tumor microenvironment,T cells operate with a metabolic disadvantage.This may be mainly due to the competition between T cells and cancer cells for limiting nutrients.It has been reported that DMF covalently modified cysteine residues of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase(GAPDH),then down-regulates aerobic glycolysis in activated myeloid and lymphoid cells,which mediates its anti-inflammatory effects.Thus we want to know if DMF can regulate cancer cell metabolism and control tumor growth.Bioinfoamatics analysis statistic data showed that significant difference of GAPDH transcripts between tumorous and non-cancerous tissues.Additionally,high GAPDH expression correlated with poor prognosis of cancer patients.Herein,we report that DMF can inhibit cancer cell proliferation and tumor growth through regulating cancer cell metabolism.Then,we solved the high resolution crystal structure of DMF and GAPDH.The results showed that DMF occupied the substrate glyceraldehyde-3-phosphate(G3P)binding region with the GAPDH,leading to substrate bind to enzyme ineffectively,thus inhibiting GAPDH enzyme activity.In this study,the widely anticancer drug doxorubicin(DOX)is loaded into Metal-Organic Frameworks nano-particles(MNPs),leading to effective drug accumulation in tumor due to EPR effect and precisely release of the drug in the tumor site by its p H sensitive instability with no side effects to the normal tissue.We treated 4T1 cells with DOX at different concentrations,we noted that DOX could inhibit the proliferation of 4T1 cells in a dose-dependent manner by inducing 4T1cells apoptosis.DOX was loaded into MNPs and it exerted good antitumor effect.CD8~+T cells play a vital role in cancer immunotherapy and can be shaped by metabolism.Avasimibe is an acyl coenzyme A-cholesterol acyltransferase(ACAT)inhibitor,which has been clinically verified safe in other phaseⅢclinical trials.It can potentiate the killing function of CD8~+T cells by modulating cholesterol metabolism.Our findings demonstrated that avasimibe combining DOX-MNPs exhibited a better efficacy than monotherapies in cancer therapy.Taken together,Our data indicated DMF occupied G3P binding region with the GAPDH,inhibiting aerobic glycolysis of cancer;Nanotechnology,immunotherapy and chemotherapy,the multiple combinations of different approaches for tumor therapy may be a great strategy to improve therapeutic efficiency,reverse drug resistance and minimize side effects. |
