CD8⁺ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8⁺ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8⁺ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226^neg CD8⁺ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8⁺ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226^−/− mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8⁺ T cell function and limits the efficacy of cancer immunotherapy.

肿瘤微环境 (TME) 内的CD8 ^{+ T 细胞暴露于最终决定功能结果的各种信号中。}在这里，我们检查了共激活受体 CD226 (DNAM-1) 在 CD8 ⁺ T 细胞功能中的作用。CD226 表达的缺失确定了健康个体外周血中存在的功能失调的 CD8 ^{+ T 细胞亚群。}这些细胞在刺激后表现出 LFA-1 活化减少、TCR 信号改变和独特的转录组程序。CD226^否定CD8 ⁺T 细胞通过涉及转录调节因子 Eomesodermin (Eomes) 的抗原特异性机制在不同来源的人和小鼠肿瘤中积累。尽管共抑制受体的表达相似，但在没有 CD226 的情况下，CD8 ⁺肿瘤浸润淋巴细胞未能对抗 PD-1 作出反应。Cd226 ^-/-小鼠的免疫检查点阻断功效受到阻碍。抗 CD137 (4-1BB) 激动剂也刺激 Eomes 依赖性 CD226 损失，这限制了这种治疗的抗肿瘤功效。因此，CD226 缺失抑制了 CD8 ⁺ T 细胞功能并限制了癌症免疫治疗的功效。