Targeting PD-1 post-translational modifications for improving cancer immunotherapy

Jie Shi , Chuan He , Li Chen , Xixin Xing , Wenyi Wei , Jinfang Zhang
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引用次数: 0

Abstract

Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.
靶向PD-1翻译后修饰改善癌症免疫治疗
程序性细胞死亡蛋白1 (PD-1)是一种重要的免疫检查点受体,主要通过与PD-L1的相互作用抑制免疫反应。肿瘤利用这种机制逃避免疫监视,定位靶向PD-1/PD-L1轴的免疫检查点抑制剂是癌症治疗的突破性进展。然而,这些疗法的总体有效性往往受到对潜在机制的不完全理解的限制。最近的研究揭示了PD-1的各种翻译后修饰(PTMs),包括泛素化,ufmy化,磷酸化,棕榈酰化和糖基化,在调节其蛋白质稳定性,定位和蛋白质-蛋白质相互作用中的关键作用。同样,这些ptm的失调可以驱动pd -1介导的免疫逃避,并有助于治疗抵抗。值得注意的是,在临床前小鼠模型和临床试验中,用小分子抑制剂或单克隆抗体(mab)靶向PD-1 PTMs已显示出增强抗肿瘤免疫的潜力。本综述重点介绍了PD-1 ptm的最新发现,并探讨了旨在调节这些修饰的新兴治疗策略。通过整合这些机制的见解,癌症免疫联合疗法的发展可以进一步合理推进,为更有效和持久的治疗提供新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell insight
Cell insight Neuroscience (General), Biochemistry, Genetics and Molecular Biology (General), Cancer Research, Cell Biology
CiteScore
2.70
自引率
0.00%
发文量
0
审稿时长
35 days
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