Targeting PHGDH reverses the immunosuppressive function in macrophages and enhances cancer immunotherapy. Targeting PHGDH reverses the immunosuppressive function in macrophages and enhances cancer immunotherapy

Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in facilitating 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) remains poorly understood. Here, we find that T helper 2 (Th2) cytokine interleukin-4 and the tumor-conditioned media increase the expression of PHGDH in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of a M2-like macrophage phenotype in the tumor microenvironment. Genetically ablating PHGDH in macrophages of tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs towards an M1-like phenotype and enhanced anti-tumor 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. Overall design: Gene expression profiling analysis of RNA-seq data obtained from Phgdhfl/fl Cx3cr1-Cre (macrophage-specific Phgdh deletion) bone marrow-derived macrophages (BMDMs) and Phgdhfl/fl BMDMs that were stimulated with AE17-tumor-conditioned medium for 24 hours. Each condition contains 4 biological replicates.

磷酸甘油酸脱氢酶（Phosphoglycerate dehydrogenase, PHGDH）已被证实是癌细胞、淋巴细胞与内皮细胞中参与大分子合成、中和氧化应激及调控甲基化反应的关键因子。然而，PHGDH在肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）中的功能目前尚不明晰。
本研究发现，辅助性T细胞2（T helper 2, Th2）型细胞因子白细胞介素-4与肿瘤条件培养基可上调巨噬细胞中PHGDH的表达，并促进具有免疫抑制功能的M2型巨噬细胞活化与增殖。
敲除PHGDH会破坏免疫抑制型巨噬细胞赖以生存的细胞代谢与线粒体呼吸功能。
机制上，PHGDH介导的丝氨酸生物合成可促进α-酮戊二酸生成，进而激活mTORC1信号通路，有助于维持肿瘤微环境中的M2样巨噬细胞表型。
在荷瘤小鼠的巨噬细胞中特异性敲除PHGDH，可抑制肿瘤生长、减少肿瘤相关巨噬细胞浸润、促使M2样肿瘤相关巨噬细胞向M1样表型转化，并增强抗肿瘤T细胞免疫。
本研究为将PHGDH作为潜在靶点，以逆转肿瘤相关巨噬细胞介导的免疫抑制、阻滞肿瘤进展提供了坚实的理论依据。
实验设计：对经AE17肿瘤条件培养基刺激24小时的Phgdhfl/fl Cx3cr1-Cre（巨噬细胞特异性Phgdh敲除）骨髓来源巨噬细胞（bone marrow-derived macrophages, BMDMs）与野生型Phgdhfl/fl骨髓来源巨噬细胞的RNA测序数据进行基因表达谱分析。每组设置4个生物学重复。