CD8 T 细胞的功能完整性与代谢重编程密切相关；因此，了解 CD8 T 细胞激活和抗肿瘤免疫的代谢基础可以为肿瘤免疫治疗提供见解。在这里，我们报告 ME2 对于小鼠 CD8 T 细胞激活和针对恶性肿瘤的免疫反应至关重要。 ME2 缺陷会抑制体外和体内 CD8 T 细胞的激活和抗肿瘤免疫反应。从机制上讲，ME2 耗尽会阻碍 TCA 循环通量，导致富马酸盐的积累。富马酸盐直接与 DAPK1 结合，并通过与 ATP 竞争结合来抑制其活性。值得注意的是，DAPK1 的药理学抑制会消除 ME2 赋予 CD8 T 细胞的抗肿瘤功能。总的来说，这些发现证明了 ME2 在调节 CD8 T 细胞代谢和效应器功能中的作用，以及富马酸作为代谢信号在抑制 DAPK1 中的意想不到的功能。版权所有 © 2024 Elsevier Inc. 保留所有权利。

The functional integrity of CD8+ T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8+ T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8+ T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8+ T cell activation and anti-tumor immune response in vitro and in vivo. Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8+ T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8+ T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.Copyright © 2024 Elsevier Inc. All rights reserved.