超过一半的高PD-L1表达的肿瘤患者对抗PD-1/PD-L1治疗没有反应，其潜在机制尚待阐明。在这里，我们表明，表达 PD-L1 的肿瘤对抗 PD-1 疗法的反应需要发育调节的 GTP 结合蛋白 2 (DRG2)。 DRG2 缺失增强了黑色素瘤细胞中 IFN-γ 信号传导并增加了 PD-L1 水平。然而，它抑制内体PD-L1的循环并降低表面PD-L1水平，从而导致与PD-1相互作用的缺陷。抗PD-1不会在DRG2耗尽的肿瘤内扩增效应样T细胞，也无法提高DRG2耗尽的荷瘤小鼠的存活率。队列分析显示，DRG2 蛋白水平较低的黑色素瘤患者对抗 PD-1 治疗有抵抗力。这些发现确定 DRG2 是内体 PD-L1 循环和抗 PD-1 治疗反应的关键调节因子，并为如何增加 PD-L1 表达和抗 PD-1 治疗反应之间的相关性提供了见解。© 2024 . 作者。

More than half of tumor patients with high PD-L1 expression do not respond to anti-PD-1/PD-L1 therapy, and the underlying mechanisms are yet to be clarified. Here we show that developmentally regulated GTP-binding protein 2 (DRG2) is required for response of PD-L1-expressing tumors to anti-PD-1 therapy. DRG2 depletion enhanced IFN-γ signaling and increased the PD-L1 level in melanoma cells. However, it inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 levels, which led to defects in interaction with PD-1. Anti-PD-1 did not expand effector-like T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis revealed that patients bearing melanoma with low DRG2 protein levels were resistant to anti-PD-1 therapy. These findings identify DRG2 as a key regulator of recycling of endosomal PD-L1 and response to anti-PD-1 therapy and provide insights into how to increase the correlation between PD-L1 expression and response to anti-PD-1 therapy.© 2024. The Author(s).