Zhao Haoming, Zhang Zhen, Zhang Chaojun, Ma Hexin, Wan Qingqing, Zhao Xinran, Wang Xu, Yan Ming, Guo Haiyan, Zhang Jianjun, Chen Wantao
Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Research Institute of Stomatology, Shanghai, China.
J Exp Clin Cancer Res. 2025 Jul 2;44(1):181. doi: 10.1186/s13046-025-03438-z.
Most cancers, including head and neck squamous cell carcinoma (HNSCC), frequently exhibit an approximately 80% lack of response to immune checkpoint blockade (ICB) therapy, largely attributed to hypoxia-induced tumor immune suppression. Although hypoxia is known to upregulate PD-L1 expression, the key mechanisms by which it enhances PD-L1 membrane localization and high expression remain elusive.
We investigated the molecular mechanisms by which hypoxia enhances PD-L1 membrane localization in HNSCC cells. Additionally, we tested the efficacy of combining an anti-PD-1 antibody with the NMT1 inhibitor PCLX-001 in HNSCC xenograft mice and conducted a retrospective clinical study to assess NMT1 as a prognostic biomarker.
Our study revealed that hypoxia-inducible factor-1α (HIF1α) upregulates N-myristoyltransferase 1 (NMT1), which mediates the myristoylation of calcineurin B homologous protein 1 (CHP1). Myristoylated CHP1 binds to PD-L1, facilitating its rapid translocation to the cell membrane and increasing PD-L1-mediated immune evasion. The NMT1 inhibitor low-dose PCLX-001 blocks CHP1 myristoylation, disrupting excessive PD-L1 membrane localization and attenuating cancer immune suppression. In HNSCC xenograft mice, administering an anti-PD-1 antibody combined with low-dose PCLX-001 via intratumoral injection significantly improved the treatment response rate and produced synergistic anticancer effects with no significant weight loss. Furthermore, our retrospective clinical study demonstrated that NMT1 protein levels can serve as an independent prognostic biomarker for HNSCC.
These findings provide robust theoretical support for the translational application of combining NMT1 inhibitors and ICB therapy in cancers under hypoxic conditions. This study introduces a combined cancer therapy strategy named "spatial blockade plus signaling inhibition of PD-L1."
大多数癌症，包括头颈部鳞状细胞癌（HNSCC），对免疫检查点阻断（ICB）治疗常常表现出约80%的低反应率，这主要归因于缺氧诱导的肿瘤免疫抑制。尽管已知缺氧会上调程序性死亡受体配体1（PD-L1）的表达，但其增强PD-L1膜定位和高表达的关键机制仍不清楚。
我们研究了缺氧增强HNSCC细胞中PD-L1膜定位的分子机制。此外，我们在HNSCC异种移植小鼠中测试了抗程序性死亡蛋白1（PD-1）抗体与N-肉豆蔻酰转移酶1（NMT1）抑制剂PCLX-001联合使用的疗效，并进行了一项回顾性临床研究，以评估NMT1作为一种预后生物标志物。
我们的研究表明，缺氧诱导因子-1α（HIF1α）上调N-肉豆蔻酰转移酶1（NMT1），后者介导钙调神经磷酸酶B同源蛋白1（CHP1）的肉豆蔻酰化。肉豆蔻酰化的CHP1与PD-L1结合，促进其快速转运至细胞膜，并增加PD-L1介导的免疫逃逸。NMT1抑制剂低剂量PCLX-001可阻断CHP1的肉豆蔻酰化，破坏过度的PD-L1膜定位，并减弱癌症免疫抑制。在HNSCC异种移植小鼠中，通过瘤内注射给予抗PD-1抗体联合低剂量PCLX-001可显著提高治疗反应率，并产生协同抗癌作用，且无明显体重减轻。此外，我们的回顾性临床研究表明，NMT1蛋白水平可作为HNSCC的独立预后生物标志物。
这些发现为在缺氧条件下将NMT1抑制剂与ICB治疗联合应用于癌症的转化应用提供了有力的理论支持。本研究引入了一种名为“PD-L1的空间阻断加信号抑制”的联合癌症治疗策略。
