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

Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H. Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

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 promotes α-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.

Original languageEnglish
Pages (from-to)448-465
Number of pages18
JournalCellular and Molecular Immunology
Volume21
Issue number5
Early online date2024
DOIs
Publication statusPublished - May 2024

Austrian Fields of Science 2012

  • 301902 Immunology
  • 106052 Cell biology
  • 106023 Molecular biology
  • 301904 Cancer research

Keywords

  • de novo serine synthesis
  • mTORC1
  • PHGDH
  • protumorigenic
  • tumor-associated macrophages, metabolomics
  • α-ketoglutarate

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