神经酰胺破坏TM9SF2-PGK1轴，重新定向PD-L1运输，增强抗肿瘤免疫力
Ceramide disrupts TM9SF2-PGK1 axis to redirect PD-L1 trafficking and enhance antitumor immunity.
摘要(中文译文)
程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）轴是癌症免疫治疗的基石，然而PD-L1在内体循环与溶酶体降解途径之间的动态转运限制了持久应答。通过针对鞘糖脂代谢的CRISPR筛选，我们鉴定出跨膜9超家族成员2（TM9SF2）是PD-L1水平的关键调控因子。TM9SF2 orchestration了一种双重机制：它招募磷酸甘油酸激酶1（PGK1）促进PD-L1循环至质膜，同时瓦解亨廷顿蛋白相互作用蛋白1相关蛋白（HIP1R）介导的溶酶体降解途径。遗传学或药理学干扰TM9SF2-PGK1复合物可降低PD-L1水平并增强抗肿瘤免疫。此外，内源性神经酰胺种类Cer(d18:1/26:0)使该复合物不稳定，触发PD-L1溶酶体破坏并增强抗肿瘤免疫。这些发现描绘了内体网络内一种由神经酰胺门控的分选机制，揭示了一个可成药的代谢开关，用以破坏免疫逃逸并放大检查点阻断疗效。
Abstract
The programmed cell death protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) axis represents a cornerstone of cancer immunotherapy, yet the dynamic shuttling of PD-L1 between endosomal recycling and lysosomal degradation routes limits durable responses. Using a CRISPR screen targeting glycosphingolipid metabolism, we identify transmembrane 9 superfamily member 2 (TM9SF2) as a key regulator of PD-L1 levels. TM9SF2 orchestrates a dual mechanism: it recruits phosphoglycerate kinase 1 (PGK1) to promote PD-L1 recycling to the plasma membrane while dismantling the huntingtin-interacting protein 1-related protein (HIP1R)-mediated lysosomal degradation pathway. Genetic or pharmacological disruption of the TM9SF2-PGK1 complex depletes PD-L1 levels and boosts antitumor immunity. Further, the endogenous ceramide species Cer(d18:1/26:0) destabilizes this complex, triggering PD-L1 lysosomal destruction and potentiating antitumor immunity. These findings delineate a ceramide-gated sorting mechanism within the endosomal network, revealing a druggable metabolic switch to disrupt immune evasion and amplify checkpoint blockade efficacy.
如何引用
AMA
Yi Zheng, Fan Yang, Mengmeng Wang, Zhiying Wang, Xindan Zhang, Chenxin Huo, et al. Ceramide disrupts TM9SF2-PGK1 axis to redirect PD-L1 trafficking and enhance antitumor immunity.. Nature communications. 2026; doi:10.1038/s41467-026-70764-x.
APA
Yi Zheng, Fan Yang, Mengmeng Wang, Zhiying Wang, Xindan Zhang, Chenxin Huo, et al (2026). Ceramide disrupts TM9SF2-PGK1 axis to redirect PD-L1 trafficking and enhance antitumor immunity.. Nature communications. https://doi.org/10.1038/s41467-026-70764-x
GB/T 7714
Yi Zheng, Fan Yang, Mengmeng Wang, Zhiying Wang, Xindan Zhang, Chenxin Huo, et al. Ceramide disrupts TM9SF2-PGK1 axis to redirect PD-L1 trafficking and enhance antitumor immunity.[J]. Nature communications, 2026 doi:10.1038/s41467-026-70764-x.
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