mTORC1型
表型
癌症研究
肿瘤微环境
信号转导
生物
下调和上调
细胞因子
免疫学
细胞生物学
PI3K/AKT/mTOR通路
基因
肿瘤细胞
生物化学
作者
Zhengnan Cai,Li Wan,Sonja Hager,Jayne Louise Wilson,Leila Afjehi-Sadat,Elke H. Heiß,Thomas Weichhart,Petra Heffeter,Wolfram Weckwerth
标识
DOI:10.1038/s41423-024-01134-0
摘要
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.
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