As an immune checkpoint, programmed cell death 1 (PD‐1) and its ligand (PD‐L1) pathway plays a crucial role in CD8⁺ cytotoxic T lymphocytes (CTL) activation and provides antitumor responses. The N‐glycans of PD‐1 and PD‐L1 are highly core fucosylated, which are solely catalyzed by the core fucosyltransferase (Fut8). However, the precise biological mechanisms underlying effects of core fucosylation of PD‐1 and PD‐L1 on CTL activation have not been fully understood. In this study, we found that core fucosylation was significantly upregulated in lung adenocarcinoma. Compared to those of Fut8^+/+OT‐I mice, the lung adenocarcinoma formation induced by urethane was markedly reduced in Fut8^−/−OT‐I mice. De‐core fucosylation of PD‐1 compromised its expression on Fut8^−/− CTL, resulted in enhanced Fut8^−/− CTL activation and cytotoxicity, leading to more efficient tumor eradication. Indeed, loss of core fucosylation significantly enhanced the PD‐1 ubiquitination and in turn led to the degradation of PD‐1 in the proteasome. Our current work indicates that inhibition of core fucosylation is a unique strategy to reduce PD‐1 expression for the antilung adenocarcinoma immune therapy in the future.

中文翻译：

---

核心岩藻糖基化的丧失通过增加PD-1降解来增强细胞毒性T淋巴细胞的抗癌活性。

作为免疫检查点，程序性细胞死亡1（PD-1）及其配体（PD-1L）途径在CD8 ⁺细胞毒性T淋巴细胞（CTL）激活中起关键作用，并提供抗肿瘤反应。PD-1和PD-1L的N-聚糖是高度岩藻糖基化的，仅由核心岩藻糖基转移酶（Fut8）催化。但是，尚未完全了解PD-1和PD-1L的核心岩藻糖基化作用对CTL活化的确切生物学机制。在这项研究中，我们发现核心岩藻糖基化在肺腺癌中显着上调。与Fut8 ^{+ / +} OT-I小鼠相比，Fut8 ^-/-氨基甲酸乙酯诱导的肺腺癌形成明显减少OT‐I小鼠。PD-1的去核心岩藻糖基化损害了其在Fut8 ^-/- CTL上的表达，导致增强的Fut8 ^-/- CTL活化和细胞毒性，从而更有效地根除了肿瘤。确实，核心岩藻糖基化的丧失显着增强了PD-1泛素化，进而导致蛋白酶体中PD-1的降解。我们目前的工作表明，抑制核心岩藻糖基化是减少抗肺腺癌免疫疗法中PD-1表达的独特策略。