胶质母细胞瘤是成人最常见的恶性脑肿瘤。细胞可塑性和分化差的特征导致肿瘤在治疗后快速复发。此外，免疫抑制微环境被证明是免疫治疗方法的主要障碍。支链氨基酸转氨酶 1 (BCAT1) 是一种代谢酶，可将支链氨基酸转化为支链酮酸，消耗细胞 α-酮戊二酸并产生谷氨酸。 BCAT1 被证明可以促进胶质母细胞瘤和其他癌症的生长；然而，其致癌机制仍知之甚少。在这里，我们表明 BCAT1 对于维持胶质母细胞瘤细胞的低分化状态至关重要，并且其低表达与分化程度较高的胶质母细胞瘤表型相关。此外，将原位肿瘤注射到免疫活性小鼠体内表明，脑微环境足以诱导体内 Bcat1-KO 肿瘤的分化。我们将向分化细胞状态的转变与 TET 去甲基酶活性的增加以及神经元分化基因的低甲基化和激活联系起来。此外，Bcat1 的敲除减弱了免疫抑制，允许 CD8 细胞毒性 T 细胞广泛浸润并完全消除肿瘤生长。对免疫缺陷小鼠的进一步分析表明，BCAT1-KO 后的肿瘤细胞分化和免疫调节都有助于长期抑制肿瘤生长。总之，我们的研究揭示了 BCAT1 通过抑制肿瘤细胞分化和维持免疫抑制环境来促进胶质母细胞瘤生长的关键作用。这些发现为通过抑制 BCAT1 来靶向胶质母细胞瘤提供了一种新的治疗途径。© 作者 2023。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) is a metabolic enzyme that converts branched-chain amino acids into branched-chain keto acids, depleting cellular α-ketoglutarate and producing glutamate. BCAT1 was shown to drive the growth of glioblastoma and other cancers; however, its oncogenic mechanism remains poorly understood. Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of TET demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8 + cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. In summary, our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.