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

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’-tiRNA Gly 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 Gly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5’-tiRNA Gly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5’-tiRNA Gly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5’-tiRNA Gly 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 Gly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy. Conclusion Our findings indicate that targeting 5’-tiRNA Gly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients.