胶质母细胞瘤（GBM）是一种最致命的脑癌，它特征为高度血管生成和免疫抑制性恶性肿瘤。虽然免疫检查点阻断药物已经革新了癌症治疗，然而在GBM的治疗中，它们的疗效远低于预期甚至无效。在这里，我们揭示了胶质瘤衍生内皮细胞（GdECs）的基因组特征与免疫抑制状态以及胶质瘤患者预后不良相关。建立了GdECs分化的离体模型进行药物筛选，并确定cAMP活化剂可以通过诱导氧化应激有效阻断GdECs的形成。cAMP活化剂在体内影响GdECs分化，使肿瘤血管恢复正常，并改变免疫谱特别是增加了CD8+效应T细胞的流入和功能。GdECs和PD-1的双重阻断会导致肿瘤消退，并建立抗肿瘤免疫记忆。我们的研究揭示了GBM的内皮细胞转分化塑造了内皮免疫细胞屏障，并支持将GdECs阻断与免疫治疗相结合的临床开发。

Glioblastoma (GBM) is the deadliest form of brain cancer, characterized as a highly angiogenetic and immunosuppressive malignancy. Although immune checkpoint blockades have revolutionized cancer therapy, their therapeutic efficacy in GBM has been far less than expected or even ineffective. Here, we reveal that the genomic signature of glioma-derived endothelial cells (GdECs) correlates with an immunosuppressive state and poor prognosis of glioma patients. In vitro model of GdECs differentiation is established for drug screening, and we identify that cAMP activators could effectively block the GdECs formation by inducing oxidative stress. cAMP activator impairs the GdECs differentiation in vivo, normalizes the tumor vessels, and alters the immune profile, especially increasing the influx and function of CD8+ effector T cells. The dual blockade of GdECs and PD-1 induces tumor regression and establishes anti-tumor immune memory. Our study reveals that endothelial transdifferentiation of GBM shapes an endothelial immune cell barrier and supports the clinical development of combining GdECs blockade and immunotherapy for GBM.