Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling
- Author(s)
- Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H. Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth
- 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.
- Organisation(s)
- Department of Food Chemistry and Toxicology, Core Facility Shared Services UBB, Department of Pharmaceutical Sciences, Functional and Evolutionary Ecology, Research Platform Vienna Metabolomics Center
- External organisation(s)
- Molecular Systems Biology Lab (MOSYS), Medizinische Universität Wien, Vienna Doctoral School of Ecology and Evolution, Universität Wien
- Journal
- Cellular and Molecular Immunology
- ISSN
- 1672-7681
- DOI
- https://doi.org/10.1038/s41423-024-01134-0
- Publication date
- 2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301902 Immunology, 106052 Cell biology, 106023 Molecular biology, 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- Immunology and Allergy, Immunology, Infectious Diseases
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/targeting-phgdh-reverses-the-immunosuppressive-phenotype-of-tumorassociated-macrophages-through-ketoglutarate-and-mtorc1-signaling(7b506938-f803-40a3-8ba1-47c538f7d07c).html