CD8 T 细胞激活导致效应 T 细胞 (Teffs) 快速增殖和分化，从而介导抗肿瘤免疫。尽管有氧糖酵解在 CD8 Teffs 中优先被激活，但在低葡萄糖和酸性肿瘤微环境 (TME) 中调节 CD8 T 细胞葡萄糖摄取的机制仍知之甚少。在这里，我们报告在 CD8 T 细胞激活和抗肿瘤免疫过程中葡萄糖转运蛋白 GLUT10 的丰度增加。具体来说，GLUT10 缺乏会抑制肿瘤浸润 CD8 T 细胞的葡萄糖摄取、糖酵解和抗肿瘤效率。单独补充葡萄糖不足以挽救 TME 中 CD8 T 细胞的抗肿瘤功能和葡萄糖摄取。通过分析肿瘤环境代谢物，我们发现高浓度的乳酸通过直接与 GLUT10 的胞内基序结合，降低了 CD8 T 细胞的葡萄糖摄取、激活和抗肿瘤作用。通过模拟肽 PG10.3 破坏乳酸和 GLUT10 的相互作用，促进 CD8 T 细胞葡萄糖利用、增殖和抗肿瘤功能。 PG10.3和GLUT1抑制或抗程序性细胞死亡1抗体治疗的组合显示出协同抗肿瘤作用。总之，我们的数据表明，CD8 T 细胞的葡萄糖摄取选择性地需要 GLUT10，并确定 TME 积累的乳酸通过直接与 GLUT10 结合并降低其葡萄糖转运能力来抑制 CD8 T 细胞效应功能。最后，我们的研究表明破坏乳酸-GLUT10 结合是增强 CD8 T 细胞介导的抗肿瘤作用的一种有前景的治疗策略。

CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.