免疫疗法的功效受限于肿瘤血管发育异常、缺乏 T 细胞的输送和渗透进入肿瘤的情况。我们在此报告磷酸甘油酸脱氢酶 (PHGDH) 介导的内皮细胞 (EC) 代谢通过形成缺氧和免疫敌视的血管微环境，引导着胶质母细胞瘤 (GBM) 对嵌合抗原受体 (CAR)-T 细胞免疫疗法的抵抗。我们对人类和小鼠 GBM 肿瘤的代谢组和转录组分析表明，在肿瘤 EC 中 PHGDH 表达和丝氨酸代谢被优先改变。肿瘤微环境信号诱导 ATF4 介导 EC 中的 PHGDH 表达，触发一个依赖于氧化还原的机制，调节内皮糖酵解，并导致 EC 过度生长。在 EC 中的基因 PHGDH 缺失有助于修剪过多的血管，消除肿瘤内部缺氧，提高 T 细胞对肿瘤的渗透。PHGDH 的抑制激活抗肿瘤 T 细胞免疫力，并使 GBM 对 CAR T 细胞疗法敏感。因此，通过针对 PHGDH 重编内皮代谢，可能提供改善基于 T 细胞的免疫疗法的独特机会。 版权所有 ©2023 Elsevier Inc.

The efficacy of immunotherapy is limited by the paucity of T cells delivered and infiltrated into the tumors through aberrant tumor vasculature. Here, we report that phosphoglycerate dehydrogenase (PHGDH)-mediated endothelial cell (EC) metabolism fuels the formation of a hypoxic and immune-hostile vascular microenvironment, driving glioblastoma (GBM) resistance to chimeric antigen receptor (CAR)-T cell immunotherapy. Our metabolome and transcriptome analyses of human and mouse GBM tumors identify that PHGDH expression and serine metabolism are preferentially altered in tumor ECs. Tumor microenvironmental cues induce ATF4-mediated PHGDH expression in ECs, triggering a redox-dependent mechanism that regulates endothelial glycolysis and leads to EC overgrowth. Genetic PHGDH ablation in ECs prunes over-sprouting vasculature, abrogates intratumoral hypoxia, and improves T cell infiltration into the tumors. PHGDH inhibition activates anti-tumor T cell immunity and sensitizes GBM to CAR T therapy. Thus, reprogramming endothelial metabolism by targeting PHGDH may offer a unique opportunity to improve T cell-based immunotherapy.Copyright © 2023 Elsevier Inc. All rights reserved.