肿瘤微环境中广泛表达的白细胞介素-6（IL-6）与患者预后不良相关。在这里，我们证明了抑制细胞因子信号抑制因子3（SOCS3）在T细胞中的缺失通过赋予小鼠和人体模型中IL-6的抗肿瘤功能来增强抗肿瘤免疫反应。在Socs3缺陷的CD8+ T细胞中，IL-6上调I型干扰素（IFN）调控基因的表达，并增强T细胞的抗肿瘤效应，同时通过改变线粒体适应性来提高线粒体膜电位和活性氧（ROS）水平，并促进能量状态中的代谢性糖酵解。此外，Socs3缺陷减少调节性T细胞，增加T辅助1细胞（Th1细胞）。在人源化小鼠模型中，人源化嵌合抗原受体T（CAR-T）细胞中的SOCS3敲除表现出强烈的抗肿瘤反应。因此，SOCS3基因破坏为改善采用T细胞疗法的治疗效果提供了一条途径。版权所有©2023作者。由Elsevier Inc.出版。保留所有权利。

Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.