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Tumor-associated macrophages(TAMs)and Myeloid derived suppressor cells(MDSCs)contribute greatly to hallmarks of cancer.Several studies have shown that Notch signaling is critically involved in myeloid cells development and macrophage activation,however the exact downstream mechanisms mediating these effects remained unclear.In this study,we show that forced Notch activation in myeloid cells by conditional overexpressing Notch1 intracellular domain(NIC)resulted in deficient G-MDSCs and promoting maturation of TAMs,leading to repressed growth of transplanted tumors in mice.The M-MDSCs could differentiate into G-MDSCs,macrophages or DCs.The further study indicated that Notch signaling decreased the differentiation of M-MDSCs to G-MDSCs and increased that to mature TAMs,which presented M1-like phenotype compared to immature TAMs.The mechanism research demonstrated Notch signaling could suppress the glycolysis and lactate uptake by inhibiting the expression of Glut1 and MCT2 in MDSCs.Increasing glucose and extra added lactate during MDSC culturing promoted G-MDSCs development and suppressed macrophages maturation,which could be totally rescued by NIC activation.In summary,our data establish a novel molecular pathway by which Notch signa ling regulates glycolysis pathway in MDSCs and TAMs development in tumor growth,and potentiate Notch activation myeloid cells as a new tool for cancer therapy.