Inhibition of 5’-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer
4 affiliations
- 1Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University
- 2Department of Pharmacy, Affiliated Hospital of Nantong University, Pharmacy School of Nantong University
- 3Center of Clinical Laboratory Medicine, Zhongda Hospital, Medical School of Southeast University
- 4Department of Hematology, Affiliated Hospital of Nantong University, Medical School of Nantong University
Abstract
Background 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. Methods and results In this study, 5’-tiRNAGly levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5’-tiRNAGly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5’-tiRNAGly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5’-tiRNAGly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5’-tiRNAGly 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’-tiRNAGly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy. Conclusion Our findings indicate that targeting 5’-tiRNAGly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients. Graphical Abstract Inhibition of 5’-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer
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BibTeX
@article{gu2026inhibition,
title = {{Inhibition of 5’-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer}},
author = {Xinliang Gu and Yu Zhang and Yang Li and Xun Li and Yuening Sun and Shuo Ma and Xinyue Qin and Yuejiao Huang and Xianjuan Shen and Ming Zheng and Quanhua Yi and Zhiyuan Tang and Shaoqing Ju},
journal = {Journal of Experimental \& Clinical Cancer Research},
year = {2026},
month = jun,
doi = {10.1186/s13046-026-03758-8},
url = {https://doi.org/10.1186/s13046-026-03758-8},
note = {CC BY},
}
RIS
TY - JOUR
TI - Inhibition of 5’-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer
AU - Xinliang Gu
AU - Yu Zhang
AU - Yang Li
AU - Xun Li
AU - Yuening Sun
AU - Shuo Ma
AU - Xinyue Qin
AU - Yuejiao Huang
AU - Xianjuan Shen
AU - Ming Zheng
AU - Quanhua Yi
AU - Zhiyuan Tang
AU - Shaoqing Ju
PY - 2026
DA - 2026/06/01
JO - Journal of Experimental & Clinical Cancer Research
DO - 10.1186/s13046-026-03758-8
UR - https://doi.org/10.1186/s13046-026-03758-8
AB - Background 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. Methods and results In this study, 5’-tiRNAGly levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5’-tiRNAGly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5’-tiRNAGly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5’-tiRNAGly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5’-tiRNAGly 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’-tiRNAGly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy. Conclusion Our findings indicate that targeting 5’-tiRNAGly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients. Graphical Abstract Inhibition of 5’-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer
SN - 1756-9966
ER -