CD8⁺ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (T_ex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally T_ex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by T_ex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in T_ex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which T_ex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.

CD8⁺ T 细胞是抗肿瘤免疫的关键介质，但在肿瘤微环境 （TME） 中持续受到 T 细胞受体刺激后，会分化为功能障碍状态，称为 T 细胞耗竭。耗竭的 T （T_ex） 细胞的特征是共抑制分子上调和多功能降低。TME 中的 T 细胞通过降低营养物质和氧气水平以及乳酸积累来经历免疫抑制代谢环境。在这里，我们表明末端 T_ex 细胞独特地上调 Slc16a11，它编码单羧酸盐转运蛋白 11 （MCT11）。T 细胞中 MCT11 的条件性缺失减少了 T_ex 细胞对乳酸的摄取并改善了其效应功能。用抗体靶向 MCT11 可减少 T_ex 细胞中乳酸的摄取，当用于治疗荷瘤小鼠时，可减少肿瘤生长。这些数据支持一个模型，其中 T_ex 细胞上调 MCT11，使它们对 TME 中高水平存在的乳酸敏感。