肿瘤浸润淋巴细胞（TIL）功能低下会导致晚期癌症的进展，并且是免疫治疗的常见目标。新出现的证据表明，在强直刺激期间，代谢不足会导致 T 细胞功能减退，但在这种情况下启动代谢重编程的信号在很大程度上尚不清楚。在这里，我们发现镍纹蛋白样 (METRNL) 是一种由肿瘤微环境 (TME) 中的免疫细胞分泌的代谢活性细胞因子，可诱导 CD8 T 细胞的生物能衰竭。 METRNL 由 CD8 T 细胞在重复刺激过程中分泌，并通过自分泌和旁分泌信号传导发挥作用。从机制上讲，METRNL 增加了 E2F 过氧化物酶体增殖物激活受体 δ (PPARδ) 活性，导致线粒体去极化和氧化磷酸化减少，从而引发补偿性生物能向糖酵解的转变。 Metrnl 消融或下调可改善 CD8 T 细胞的代谢适应性，并增强多种肿瘤模型中的肿瘤控制，证明了靶向 METRNL-E2F-PPARδ 途径支持 CD8 TIL 生物能适应性的转化潜力。版权所有 © 2024 Elsevier Inc.。预订的。

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.Copyright © 2024 Elsevier Inc. All rights reserved.