Deficiency of GLUT1 in macrophages reprograms tumor-associated macrophages to normalize tumor vasculature and retards the progression of tumors.

Tumor-associated macrophages (TAMs), a major glucose-consuming population within the tumor microenvironment (TME), utilize glycolysis to support tumor progression. Therefore, concentrating on the glycolysis of intratumoral TAMs appears to be a promising research direction for tumor therapy. In this study, we demonstrated that the key glycolytic component named glucose transporter protein 1 (GLUT1, also known as SLC2A1) is extensively expressed in TAMs and is frequently associated with tumor progression. To dissect the functions of GLUT1 in macrophages on influencing the TME, macrophage-specific Glut1 knockout mice were generated and tumor-bearing mouse models were established. It was found that macrophage-specific deletion of Glut1 retarded the development of tumors and reshaped the tumor immune microenvironment (TIME). Loss of Glut1 in macrophages limited the secretion of multiple inflammatory mediators, including IL-6, IL-10, VEGF, and CXCL2, by virtue of the GSK3β/β-catenin/CD36 signaling axis, thereby normalizing the tumor blood vessels. To pharmacologically manipulate the expression of Glut1 in macrophages, M2-PLGA@WZB117 (poly lactic-co-glycolic acid, PLGA) was constructed accordingly. Interestingly, M2-PLGA@WZB117 resulted in significant inhibition in tumor progression, accompanied by tumor vascular normalization and a concurrent increase in the infiltration of CD8+ T cells. Therefore, our study provides new insights into reprogramming TAMs to exert impacts on tumor endothelium and thus regulating the TME, thereby hindering the development of tumors.