5’-tiRNAGly的抑制通过DLST-介导的OGDHL琥珀酰化在癌症中恢复抗PD-1免疫疗法的效力
{"_":"Inhibition of 5'-tiRNA restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.","sup":["Gly"]}
摘要(中文译文)
近年来，转运RNA衍生的小RNA（tsRNAs）被认为与肿瘤进展和免疫调节相关。然而，作为tsRNAs的一个亚类，tRNA半分子（tiRNAs）在调节免疫治疗反应中的具体作用尚未被探索。本研究检测了胃癌（GC）患者的5'-tiRNA水平，发现其表达上调，尤其是在抗PD-1治疗无应答者中更为明显。5'-tiRNA水平升高还与类酮戊二酸脱氢酶（OGDHL）表达降低相关。进一步研究揭示，5'-tiRNA与DLST结合并促进OGDHL不稳定，而靶向抑制5'-tiRNA可通过赖氨酸910位点的琥珀酰化恢复OGDHL稳定性，增强三羧酸（TCA）循环活性，并减少谷氨酰胺衍生的代谢重编程。此外，研究发现5'-tiRNA可降低α-酮戊二酸脱氢酶活性，并抑制组蛋白H3赖氨酸79位点的琥珀酰化（H3K79suc），从而下调PD-L1转录并降低对PD-1抑制剂的治疗反应性。相反，抑制5'-tiRNA后恢复该表观遗传修饰可促进PD-L1转录，从而使肿瘤对抗PD-1治疗敏感。我们的研究结果表明，靶向5'-tiRNA可能是增强胃癌患者抗PD-1治疗反应性的一种有前景的策略。
Abstract
Transfer RNA-derived small RNAs (tsRNAs) have been implicated in tumor progression and immune regulation in recent years. However, the specific role of tRNA halves (tiRNAs), a subclass of tsRNAs, in modulating immunotherapy response remains unexplored. In this study, 5'-tiRNA levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5'-tiRNA levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5'-tiRNA bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5'-tiRNA restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5'-tiRNA was found to decrease the activity of α-ketoglutarate dehydrogenase and inhibit succinylation of histone H3 at lysine 79 (H3K79suc), thereby downregulating PD-L1 transcription and reducing therapeutic responsiveness to PD-1 inhibitors. Conversely, restoration of this epigenetic modification upon 5'-tiRNA inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy. Our findings indicate that targeting 5'-tiRNA may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients.
如何引用
AMA
Xinliang Gu, Yu Zhang, Yang Li, Xun Li, Yuening Sun, Shuo Ma, et al. {"_":"Inhibition of 5'-tiRNA restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.","sup":["Gly"]}. Journal of experimental & clinical cancer research : CR. 2026; doi:10.1186/s13046-026-03758-8.
APA
Xinliang Gu, Yu Zhang, Yang Li, Xun Li, Yuening Sun, Shuo Ma, et al (2026). {"_":"Inhibition of 5'-tiRNA restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.","sup":["Gly"]}. Journal of experimental & clinical cancer research : CR. https://doi.org/10.1186/s13046-026-03758-8
GB/T 7714
Xinliang Gu, Yu Zhang, Yang Li, Xun Li, Yuening Sun, Shuo Ma, et al. {"_":"Inhibition of 5'-tiRNA restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.","sup":["Gly"]}[J]. Journal of experimental & clinical cancer research : CR, 2026 doi:10.1186/s13046-026-03758-8.
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