Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages throughα-ketoglutarate and mTORC1 signaling  

作　　者：Zhengnan Cai Wan Li Sonja Hager Jayne Louise Wilson Leila Afjehi-Sadat Elke HHeiss Thomas Weichhart Petra Heffeter Wolfram Weckwerth 

机构地区：[1]Molecular Systems Biology(MOSYS),Department of Functional and Evolutionary Ecology,University of Vienna,Vienna,Austria. [2]Vienna Doctoral School of Ecology and Evolution,University of Vienna,Vienna,Austria. [3]Center for Cancer Research and Comprehensive Cancer Center,Medical University of Vienna,Vienna,Austria. [4]Department of Food Chemistry and Toxicology,Faculty of Chemistry,University of Vienna,Vienna,Austria. [5]Center for Pathobiochemistry and Genetics,Institute of Medical Genetics,Medical University of Vienna,Vienna,Austria. [6]Research Support Facility,Mass Spectrometry Unit,Faculty of Life Science,University of Vienna,Vienna,Austria. [7]Department of Pharmaceutical Sciences,University of Vienna,Vienna,Austria. [8]Vienna Metabolomics Center(VIME),University of Vienna,Vienna,Austria.

出　　处：《Cellular & Molecular Immunology》2024年第5期448-465,共18页中国免疫学杂志（英文版）

摘　　要：Phosphoglycerate dehydrogenase(PHGDH)has emerged as a crucial factor in macromolecule synthesis,neutralizing oxidative stress,and regulating methylation reactions in cancer cells,lymphocytes,and endothelial cells.However,the role of PHGDH in tumor-associated macrophages(TAMs)is poorly understood.Here,we found that the T helper 2(Th2)cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation.Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration,which are essential for immunosuppressive macrophages.Mechanistically,PHGDH-mediated serine biosynthesis promotesα-ketoglutarate production,which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment.Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth,reduced TAM infiltration,a phenotypic shift of M2-like TAMs toward an M1-like phenotype,downregulated PD-L1 expression and enhanced antitumor T-cell immunity.Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.

关 键 词：PHGDH de novo serine synthesis Α-KETOGLUTARATE mTORC1 protumorigenic tumor-associated macrophages metabolomics 

分 类 号：R73[医药卫生—肿瘤]