Inhibition of 5'-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer

  • J Exp Clin Cancer Res. 2026 Jun 13. doi: 10.1186/s13046-026-03758-8.
Xinliang Gu  #  1  2 ,  Yu Zhang  #  1 ,  Yang Li  #  1 ,  Xun Li  1 ,  Yuening Sun  3 ,  Shuo Ma  4 ,  Xinyue Qin  1 ,  Yuejiao Huang  5 ,  Xianjuan Shen  1 ,  Ming Zheng  1 ,  Quanhua Yi  3 ,  Zhiyuan Tang  6 ,  Shaoqing Ju  7
Affiliations
  • 1. Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, No.20, Nantong, Jiangsu, 226001, China.
  • 2. General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China.
  • 3. Department of Pharmacy, Affiliated Hospital of Nantong University, Pharmacy School of Nantong University, Xisi Road, No.20, Nantong, Jiangsu, 226001, China.
  • 4. Center of Clinical Laboratory Medicine, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
  • 5. Department of Hematology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
  • 6. Department of Pharmacy, Affiliated Hospital of Nantong University, Pharmacy School of Nantong University, Xisi Road, No.20, Nantong, Jiangsu, 226001, China. [email protected].
  • 7. Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, No.20, Nantong, Jiangsu, 226001, China. [email protected].
  • # Contributed equally.
PMID: 42286727 DOI: 10.1186/s13046-026-03758-8
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.

Keywords
Gastric cancer; Glutamine metabolism; OGDHL; PD-1; Succinylation; tRNA-derived small RNAs.
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