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.Howe...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.展开更多
文摘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.
