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 

作者机构：Molecular Systems Biology(MOSYS)Department of Functional and Evolutionary EcologyUniversity of ViennaViennaAustria. Vienna Doctoral School of Ecology and EvolutionUniversity of ViennaViennaAustria. Center for Cancer Research and Comprehensive Cancer CenterMedical University of ViennaViennaAustria. Department of Food Chemistry and ToxicologyFaculty of ChemistryUniversity of ViennaViennaAustria. Center for Pathobiochemistry and GeneticsInstitute of Medical GeneticsMedical University of ViennaViennaAustria. Research Support FacilityMass Spectrometry UnitFaculty of Life ScienceUniversity of ViennaViennaAustria. Department of Pharmaceutical SciencesUniversity of ViennaViennaAustria. Vienna Metabolomics Center(VIME)University of ViennaViennaAustria. 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2024年第21卷第5期

页      面：448-465页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Gerald Timelthaler Austrian Science Fund, FWF, (P32600, P30857-B28, ESP 87, P 30857) China Scholarship Council, CSC, (201908320480, 201806500012) Vienna Science and Technology Fund, WWTF, (LS18-058) 

主　　题：PHGDH de novo serine synthesis α-ketoglutarate mTORC1 protumorigenic tumor-associated macrophages,metabolomics 

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 ***,the role of PHGDH in tumor-associated macrophages(TAMs)is poorly ***,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 *** of PHGDH disrupts cellular metabolism and mitochondrial respiration,which are essential for immunosuppressive ***,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 *** 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 *** study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.