Vol. 2026 No. 3 (2026)
Articles

T RNA-derived fragments: Emerging biomarkers and targets in precision oncology

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  • Samuel Wilson,
  • Douglas Moore,
  • Barbara Walker
Samuel Wilson
Shenandoah Therapeutics, 329 Oyster Point Boulevard, 3rd Floor, South San Francisco, CA 94080, USA
Douglas Moore
Shenandoah Therapeutics, 329 Oyster Point Boulevard, 3rd Floor, South San Francisco, CA 94080, USA
Barbara Walker
Alaunos Therapeutics, Inc.8030 El Rio Street, Houston, TX 77054, USA

Published 29-05-2026

Keywords

  • transfer RNA,
  • derived fragments,
  • cancer,
  • diagnosis,
  • treatment,
  • biomarker,
  • liquid biopsy,
  • non-coding RNA
    • ...More
    Less

Copyright (c) 2026 Cambridge Science Advance

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

How to Cite

[1]
S. Wilson, D. Moore, and B. Walker, “T RNA-derived fragments: Emerging biomarkers and targets in precision oncology”, Camb. Sci. Adv., vol. 2026, no. 3, pp. 26–34, May 2026, doi: 10.62852/csa/2026/258.

Abstract

 Transfer RNA-derived fragments (t RFs) are a novel class of non-coding RNAs generated from tRNA processing. They participate in various biological processes, including the regulation of mRNA stability, translation, and epigenetic modifications. In recent years, with the advancement of high-throughput sequencing and bioinformatics, studies have revealed that t RFs are aberrantly expressed in multiple malignancies, such as gastric, colorectal, lung, and ovarian cancers. Furthermore, their dysregulation is closely associated with tumorigenesis, invasion, metastasis, and drug resistance, suggesting that t RFs hold great potential as novel diagnostic markers and prognostic indicators. This review systematically elaborates on the biogenesis, classification, and latest research progress of t RFs in cancer diagnosis and treatment. It also discusses the current challenges and future directions in this field, aiming to provide references for the clinical translation of t RFs in precision oncology.

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References

  1. SLACK F J, CHINNAIYAN A M. The role of non-coding RNAs in oncology[J]. Cell, 2019, 179(5): 1033-1055. DOI: 10.1016/j.cell.2019.10.017.
  2. XIONG Q L, ZHANG Y G. Small RNA modifications: regulatory molecules and potential applications[J]. J Hematol Oncol, 2023, 16(1): 64. DOI: 10.1186/s13045-023-01466-w.
  3. KUMAR P, KUSCU C, DUTTA A. Biogenesis and function of transfer RNA-related fragments (t RFs) [J]. Trends Biochem Sci, 2016, 41(8): 679-689. DOI: 10.1016/j.tibs.2016.05.004.
  4. ORELLANA E A, SIEGAL E, GREGORY R I. tRNA dysregulation and disease[J]. Nat Rev Genet, 2022, 23(11): 651-664. DOI: 10.1038/s41576-022-00501-9.
  5. XIE Y Y, YAO L P, YU X C, et al. Action mechanisms and research methods of tRNA-derived small RNAs[J]. Signal Transduct Target Ther, 2020, 5(1): 109. DOI: 10.1038/s41392-020-00217-4.
  6. SCHIMMEL P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis[J]. Nat Rev Mol Cell Biol, 2018, 19(1): 45-58. DOI: 10.1038/nrm.2017.77.
  7. CHEN W, PENG W, WANG R H, et al. Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells[J]. Cell Death Dis, 2024, 15(1): 102. DOI: 10.1038/s41419-024-06482-3.
  8. KUMAR P, MUDUNURI S B, ANAYA J, et al. t RF db: a database for transfer RNA fragments[J]. Nucleic Acids Res, 2015, 43(Database issue): D141-D145. DOI: 10.1093/nar/gku1138.
  9. LU S C, WEI X M, TAO L, et al. A novel tRNA-derived fragment tRF-3022b modulates cell apoptosis and M2 macrophage polarization via binding to cytokines in colorectal cancer[J]. J Hematol Oncol, 2022, 15(1): 176. DOI: 10.1186/s13045-022-01388-z.
  10. GOODARZI H, LIU X H, NGUYEN H C B, et al. Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement[J]. Cell, 2015, 161(4): 790-802. DOI: 10.1016/j.cell.2015.02.053.
  11. YANG W H, GAO K P, QIAN Y H, et al. A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes[J]. J Hematol Oncol, 2022, 15(1): 53. DOI: 10.1186/s13045-022-01270-y.
  12. FU M, GU J M, WANG M Y, et al. Emerging roles of tRNA-derived fragments in cancer[J]. Mol Cancer, 2023, 22(1): 30. DOI: 10.1186/s12943-023-01739-5.
  13. HOAGLAND M B, STEPHENSON M L, SCOTT J F, et al. A soluble ribonucleic acid intermediate in protein synthesis[J]. J Biol Chem, 1958, 231(1): 241-257.
  14. WALKER S C, ENGELKE D R. Ribonuclease P: the evolution of an ancient RNA enzyme[J]. Crit Rev Biochem Mol Biol, 2006, 41(2): 77-102. DOI: 10.1080/10409230600602634.
  15. FU Y, LEE I, LEE Y S, et al. Small non-coding transfer RNA-derived RNA fragments (t RFs): their biogenesis, function and implication in human diseases[J]. Genomics Inform, 2015, 13(4): 94-101. DOI: 10.5808/GI.2015.13.4.94.
  16. MAO M W, CHEN W N, HUANG X B, et al. Role of tRNA-derived small RNAs (ts RNAs) in the diagnosis and treatment of malignant tumours[J]. Cell Commun Signal, 2023, 21(1): 178. DOI: 10.1186/s12964-023-01199-w.
  17. LU J J, ZHU P, ZHANG X F, et al. tRNA-derived fragments: unveiling new roles and molecular mechanisms in cancer progression[J]. Int J Cancer, 2024, 155(8): 1347-1360. DOI: 10.1002/ijc.35041.
  18. WEN J T, HUANG Z H, LI Q H, et al. Research progress on the ts RNA classification, function, and application in gynecological malignant tumors[J]. Cell Death Discov, 2021, 7(1): 388. DOI: 10.1038/s41420-021-00789-2.
  19. PLIATSIKA V, LOHER P, MAGEE R, et al. MINT base v2.0: a comprehensive database for tRNA-derived fragments that includes nuclear and mitochondrial fragments from all The Cancer Genome Atlas projects[J]. Nucleic Acids Res, 2018, 46(D1): D152-D159. DOI: 10.1093/nar/gkx1075.
  20. PANOUTSOPOULOU K, DREYER T, DORN J, et al. tRNA (Gly GCC)-derived internal fragment (i-t RF-Gly GCC) in ovarian cancer treatment outcome and progression[J]. Cancers, 2021, 14(1): 24. DOI: 10.3390/cancers14010024.
  21. YU M Q, YI J N, QIU Q Z, et al. Pan-cancer tRNA-derived fragment CAT1 coordinates RBPMS to stabilize NOTCH2 mRNA to promote tumorigenesis[J]. Cell Rep, 2023, 42(11): 113408. DOI: 10.1016/j.celrep.2023.113408.
  22. HE X X, FAN X R, HUANG Y, et al. Research progress on the relationship between ts RNAs and tumors[J]. Chin J Clin Oncol, 2020, 47(2): 85-88. DOI: 10.3969/j.issn.1000-8179.2020.02.197. [Article in Chinese].
  23. HUANG Y, GE H, ZHENG M J, et al. Serum tRNA-derived fragments (t RFs) as potential candidates for diagnosis of non-triple negative breast cancer[J]. J Cell Physiol, 2020, 235(3): 2809-2824. DOI: 10.1002/jcp.29185.
  24. SUN C X, YANG F, ZHANG Y H, et al. tRNA-derived fragments as novel predictive biomarkers for trastuzumab-resistant breast cancer[J]. Cell Physiol Biochem, 2018, 49(2): 419-431. DOI: 10.1159/000492977.
  25. HE Y Z, LIU Y C, GONG J, et al. tRF-27 competitively binds to G3BPs and activates MTORC1 to enhance HER2 positive breast cancer trastuzumab tolerance[J]. Int J Biol Sci, 2024, 20(10): 3923-3941. DOI: 10.7150/ijbs.87415.
  26. ZHAO J H, CAI W H, CHEN L, et al. Mechanisms of tRNA-derived fragments (t RFs) in regulating gene expression and research progress in related diseases[J]. Journal of Nantong University (Medical Sciences), 2024, 44(1): 63-67. DOI: 10.16424/j.cnki.cn32-1807/r.2024.01.015. [Article in Chinese].
  27. XU R, DU A S, DENG X P, et al. ts RNA-Gly GCC promotes colorectal cancer progression and 5-FU resistance by regulating SPIB[J]. J Exp Clin Cancer Res, 2024, 43(1): 230. DOI: 10.1186/s13046-024-03132-6.
  28. WANG Q R, YING X W, HUANG Q Y, et al. Exploring the role of tRNA-derived small RNAs (ts RNAs) in disease: implications for HIF-1 pathway modulation[J]. J Mol Med, 2024, 102(8): 973-985. DOI: 10.1007/s00109-024-02458-0.
  29. HAN Y, PENG Y H, LIU S S, et al. tRF3008A suppresses the progression and metastasis of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner[J]. J Exp Clin Cancer Res, 2022, 41(1): 32. DOI: 10.1186/s13046-021-02190-4.
  30. CUI H P, LIU Z D, PENG L P, et al. A novel 5′tRNA-derived fragment t RF-Tyr inhibits tumor progression by targeting hn RNPD in gastric cancer[J]. Cell Commun Signal, 2025, 23(1): 88. DOI: 10.1186/s12964-025-02086-2.
  31. TONG L H, ZHANG W X, QU B C, et al. The tRNA-derived fragment-3017A promotes metastasis by inhibiting NELL2 in human gastric cancer[J]. Front Oncol, 2021, 10: 570916. DOI: 10.3389/fonc.2020.570916.
  32. ZHANG S S, GU Y Q, GE J X, et al. tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner[J]. Oncogene, 2024, 43(28): 2160-2171. DOI: 10.1038/s41388-024-03062-9.
  33. RUI T, ZHU K B, MAO Z L, et al. A novel t RF, HCETSR, derived from tRNA-glu/TTC, inhibits HCC malignancy by regulating the SPBTN1-catenin complex axis[J]. Adv Sci, 2025, 12(13): 2415229. DOI: 10.1002/advs.202415229.
  34. ZHOU Y Q, HU J J, LIU L, et al. Gly-t RF enhances LCSC-like properties and promotes HCC cells migration by targeting NDFIP2[J]. Cancer Cell Int, 2021, 21(1): 502. DOI: 10.1186/ s12935-021 -02102-8.
  35. YANG C, LEE M, SONG G, et al. t RNA(Lys)-derived fragment alleviates cisplatin-induced apoptosis in prostate cancer cells[J]. Pharmaceutics, 2021, 13(1): 55. DOI: 10.3390/ pharmaceutics 13010055.
  36. PANOUTSOPOULOU K, MAGKOU P, DREYER T, et al. tRNA-derived small RNA 3′U-tRFValCAC promotes tumour migration and early progression in ovarian cancer[J]. Eur J Cancer, 2023, 180: 134-145. DOI: 10.1016/j.ejca.2022.11.033.
  37. JIN L, ZHU C F, QIN X H. Expression profile of tRNA-derived fragments in pancreatic cancer[J]. Oncol Lett, 2019, 18(3): 3104-3114. DOI: 10.3892/ol.2019.10601.
  38. JIN H Y, YEOM J H, SHIN E, et al. 5′-tRNA (Gly (GCC)) halves generated by IRE1α are linked to the ER stress response[J]. Nat Commun, 2024, 15(1): 9273. DOI: 10.1038/s41467-024-53624-4.
  39. PICHOT F, HOGG M C, MARCHAND V, et al. Quantification of substoichiometric modification reveals global ts RNA hypomodification, preferences for angiogenin-mediated tRNA cleavage, and idiosyncratic epitranscriptomes of human neuronal cell-lines[J]. Comput Struct Biotechnol J, 2022, 21: 401-417. DOI: 10.1016/j.csbj.2022.12.020.