N4-乙酰胞苷修饰在癌症中桥接代谢重编程和免疫逃避：机制和治疗意义
N4-acetylcytidine modification bridges metabolic reprogramming and immune evasion in cancer: mechanisms and therapeutic implications.
摘要(中文译文)
N4-乙酰胞苷（ac4C）是一种由N-乙酰转移酶10（NAT10）催化、在进化上保守的RNA修饰，是真核生物mRNA中已知唯一的乙酰化修饰。近年研究表明，ac4C修饰通过调控mRNA稳定性和翻译效率，在肿瘤进展中发挥多方面作用。值得注意的是，新近证据显示，NAT10介导的ac4C修饰同时协调肿瘤代谢重编程和免疫逃逸，这两个癌症标志性特征日益被认为相互关联。在代谢调控方面，ac4C修饰增强关键糖酵解酶的稳定性和翻译，包括己糖激酶（HK1/2）、烯醇化酶1（ENO1）、乳酸脱氢酶A（LDHA）和磷酸甘油酸变位酶1（PGAM1），从而促进Warburg效应。同时，ac4C修饰通过多种机制促进免疫逃逸，包括上调PD-L1表达、抑制T细胞功能和抑制I型干扰素信号传导。重要的是，糖酵解驱动的乳酸积累形成免疫抑制性肿瘤微环境，提示ac4C作为连接代谢重编程与免疫逃逸的分子桥梁。使用Remodelin等抑制剂靶向NAT10已显示出良好的临床前疗效，尤其是与免疫检查点抑制剂联合使用时。本综述全面总结了目前对ac4C修饰在肿瘤代谢和免疫中作用的认识，重点阐述了ac4C介导的代谢-免疫交互对话，并讨论了靶向该修饰用于肿瘤治疗的治疗潜力。我们还重点介绍了关于ac4C在人mRNA中的化学计量比、ac4C在肿瘤微环境中细胞类型特异性功能，以及涵盖非编码RNA和与包括m5C、假尿苷和m6Am在内的其他RNA修饰交互对话的不断扩展的调控网络等方面的新兴争议。
Abstract
N4-acetylcytidine (ac4C) is an evolutionarily conserved RNA modification catalyzed by N-acetyltransferase 10 (NAT10), representing the sole known acetylation modification in eukaryotic mRNA. Recent studies have revealed that ac4C modification plays multifaceted roles in cancer progression by regulating mRNA stability and translation efficiency. Notably, emerging evidence demonstrates that NAT10-mediated ac4C modification simultaneously orchestrates tumor metabolic reprogramming and immune evasion, two hallmarks of cancer that are increasingly recognized as interconnected processes. In metabolic regulation, ac4C modification enhances the stability and translation of key glycolytic enzymes, including hexokinase (HK1/2), enolase 1 (ENO1), lactate dehydrogenase A (LDHA), and phosphoglycerate mutase 1 (PGAM1), thereby promoting the Warburg effect. Concurrently, ac4C modification facilitates immune evasion through multiple mechanisms, including upregulation of PD-L1 expression, suppression of T cell function, and inhibition of type I interferon signaling. Importantly, glycolysis-driven lactate accumulation creates an immunosuppressive tumor microenvironment, suggesting that ac4C serves as a molecular bridge connecting metabolic reprogramming to immune escape. Targeting NAT10 with inhibitors such as Remodelin has shown promising preclinical efficacy, particularly when combined with immune checkpoint inhibitors. This review comprehensively summarizes the current understanding of ac4C modification in tumor metabolism and immunity, highlights the metabolic-immune crosstalk mediated by ac4C, and discusses the therapeutic potential of targeting this modification for cancer treatment. We also highlight emerging controversies regarding ac4C stoichiometry in human mRNA, cell-type-specific functions of ac4C in the tumor microenvironment, and the expanding regulatory network encompassing non-coding RNAs and crosstalk with other RNA modifications including m5C, pseudouridine, and m6Am.
如何引用
AMA
Ming-Zhu Jin, Wen Di. N4-acetylcytidine modification bridges metabolic reprogramming and immune evasion in cancer: mechanisms and therapeutic implications.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1820962.
APA
Ming-Zhu Jin, Wen Di (2026). N4-acetylcytidine modification bridges metabolic reprogramming and immune evasion in cancer: mechanisms and therapeutic implications.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1820962
GB/T 7714
Ming-Zhu Jin, Wen Di. N4-acetylcytidine modification bridges metabolic reprogramming and immune evasion in cancer: mechanisms and therapeutic implications.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1820962.
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