GlycoRNA in Cancer: Biogenesis, Mechanistic Links to Tumor Biology, and Clinical Translation
DOI:
https://doi.org/10.62382/jcbt.v3i2.116Keywords:
Glycorna, Cancer glycobiology, Small extracellular vesicles, Siglec, Liquid biopsy, Tumor immunologyAbstract
GlycoRNAs are an emerging class of glycoconjugates in which selected small noncoding RNAs carry glycans and can be displayed at the cell surface. Their discovery has expanded the conceptual scope of glycobiology by introducing RNA as a previously unrecognized glycosylated scaffold and by placing it within the extracellular glycan-rich interface involved in cell communication, immune regulation, and disease-associated signaling. Increasing evidence suggests that glycoRNAs may participate in several biologically important processes, including extracellular signaling, immune modulation, and intercellular communication, and may have particular relevance to cancer biology. In this review, we summarize current knowledge of glycoRNA biogenesis, molecular features, detection strategies, and biological functions, with a focus on their potential roles in tumor progression and their translational promise as biomarkers and therapeutic targets.
Downloads
References
Pinho SS, Reis CA. Glycosylation in cancer: Mechanisms and clinical implications. Nature Reviews Cancer. 2015, 15(9), 540-555. DOI: 10.1038/nrc3982
Reily C, Stewart TJ, Renfrow MB, Novak J. Glycosylation in health and disease. Nature Reviews. Nephrology. 2019, 15(6), 346-366. DOI: 10.1038/s41581-019-0129-4
He MY, Zhou XX, Wang X. Glycosylation: Mechanisms, biological functions and clinical implications. Signal Transduction and Targeted Therapy. 2024, 9(1), 194. DOI: 10.1038/s41392-024-01886-1
Stanley P. Genetics of glycosylation in mammalian development and disease. Nature Reviews. Genetics. 2024, 25(10), 715-729. DOI: 10.1038/s41576-024-00725-x
Munkley J, Elliott DJ. Hallmarks of glycosylation in cancer. Oncotarget. 2016, 7(23), 35478-35489. DOI: 10.18632/oncotarget.8155
Nachtergaele S, Krishnan Y. New vistas for cell-surface glycornas. The New England Journal of Medicine. 2021, 385(7), 658-660. DOI: 10.1056/NEJMcibr2108679
Flynn RA, Pedram K, Malaker SA, Batista PJ, Smith BAH, Johnson AG, et al. Small RNAs are modified with N-glycans and displayed on the surface of living cells. Cell. 2021, 184(12), 3109-3124.e22. DOI: 10.1016/j.cell.2021.04.023
Liu YS, Miao YL, Dou Y, Yang ZH, Sun W, Zhou X, et al. Processing of N-glycans in the ER and Golgi influences the production of surface sialylated glycoRNA. Glycoconjugate Journal. 2024, 41(6), 361-370. DOI: 10.1007/s10719-024-10171-w
Xin BK, Chen JJ, Hu X, Yang JT, Wang XY, Wang ZQ, et al. GlycoRNAs are abundant in glioma and involved in glioma cell proliferation. Oncogenesis. 2025, 14(1), 29. DOI: 10.1038/s41389-025-00570-5
Ren TJ, Zhang YZ, Tong YX, Zhang Q, Wang TH, Wang Y, et al. FRET imaging of glycoRNA on small extracellular vesicles enabling sensitive cancer diagnostics. Nature Communications. 2025, 16(1), 3391. DOI: 10.1038/s41467-025-58490-2
Li JJ, Yue S, Gao ZY, Hu WH, Liu ZL, Xu GQ, et al. Novel approach to enriching glycosylated RNAs: Specific capture of glycornAs via solid-phase chemistry. Analytical Chemistry. 2023, 95(32), 11969-11977. DOI: 10.1021/acs.analchem.3c01630
Graziano VR, Porat J, Ah Kioon MD, Mejdrová I, Matz AJ, Lebedenko CG, et al. RNA N-glycosylation enables immune evasion and homeostatic efferocytosis. Nature. 2025, 645(8081), 784-792. DOI: 10.1038/s41586-025-09310-6
Zhang NN, Tang WW, Torres L, Wang XJ, Ajaj Y, Zhu L, et al. Cell surface RNAs control neutrophil recruitment. Cell. 2024, 187(4), 846-860e17. DOI: 10.1016/j.cell.2023.12.033
Zheng CX, Ao Y, Zhang Z, Mei SQ, Hafeez A, Teng WK, et al. GlycoRNAdb: A database of glycoRNA sequences, structures, abundance, and glycan information across tissues and cell lines. Nucleic Acids Research. 2026, 54(D1), D158-D167. DOI: 10.1093/nar/gkaf1246
Ma Y, Guo WJ, Mou QB, Shao XL, Lyu MK, Garcia V, et al. Spatial imaging of glycoRNA in single cells with ARPLA. Nature Biotechnology. 2024, 42(4), 608-616. DOI: 10.1038/s41587-023-01801-z
Xie YX, Chai PY, Till NA, Hemberger H, Lebedenko CG, Porat J, et al. The modified RNA base acp(3)U is an attachment site for N-glycans in glycoRNA. Cell. 2024, 187(19), 5228-5237.e12. DOI: 10.1016/j.cell.2024.07.044
Li Y, Qian YS, Li X, Lei TH, McGraw H, Monaghan-Nichols P, et al. Lectin-based detection and expression profiling of native glycoRNAs. Scientific Reports. 2026, 16(1), 9031. DOI: 10.1038/s41598-026-40291-2
Chai P, Lebedenko CG, Flynn RA. RNA crossing membranes: Systems and mechanisms contextualizing extracellular RNA and cell surface glycoRNAs. Annual Review of Genomics and Human Genetics. 2023, 24, 85-107. DOI: 10.1146/annurev-genom-101722-101224
Sharma S, Jiao XF, Yang J, Kwan KY, Kiledjian M. Extracellular exosomal RNAs are glyco-modified. Nature Cell Biology. 2025, 27(6), 983-991. DOI: 10.1038/s41556-025-01682-1
Porat J, Flynn RA. Cell surface RNA biology: New roles for RNA binding proteins. Trends in Biochemical Sciences. 2025, 50(5), 402-416. DOI: 10.1016/j.tibs.2025.03.005
Li ZS, Joshi BS, Yin HB, Wijdeven RH, Koç A, Zijlmans DW, et al. Cell-surface RNA forms ternary complex with RNA-binding proteins and heparan sulfate to recruit immune receptors. Molecular Cell. 2025, 85(24), 4633-4650.e11. DOI: 10.1016/j.molcel.2025.11.020
Perr J, Langen A, Almahayni K, Nestola G, Chai P, Lebedenko CG, et al. RNA-binding proteins and glycoRNAs form domains on the cell surface for cell-penetrating peptide entry. Cell. 2025, 188(7), 1878-1895.e25. DOI: 10.1016/j.cell.2025.01.040
Saxon E, Bertozzi CR. Cell surface engineering by a modified Staudinger reaction. Science. 2000, 287(5460), 2007-2010. DOI: 10.1126/science.287.5460.2007
Chai P, Kheiri S, Kuo A, Shah J, Kageler L, Ge R, et al. GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling. Nature. 2026, 651(8106), 808-818. DOI: 10.1038/s41586-025-10052-8
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011, 144(5), 646-674. DOI: 10.1016/j.cell.2011.02.013
Kerbel RS. Tumor angiogenesis. The New England Journal of Medicine. 2008, 358(19), 2039-2049. DOI: 10.1056/NEJMra0706596
Rambaruth ND, Dwek MV. Cell surface glycan-lectin interactions in tumor metastasis. Acta Histochemica. 2011. 113(6), 591-600. DOI: 10.1016/j.acthis.2011.03.001
Borsig L. Selectins in cancer immunity. Glycobiology. 2018, 28(9), 648-655. DOI: 10.1093/glycob/cwx105
Sun JW, Lu Q, Sanmamed MF, Wang J. Siglec-15 as an emerging target for next-generation cancer immunotherapy. Clinical Cancer Research. 2021, 27(3), 680-688. DOI: 10.1158/1078-0432.CCR-19-2925
Laubli H, Nalle SC, Maslyar D. Targeting the siglec-sialic acid immune axis in cancer: Current and future approaches. Cancer Immunology Research. 2022. 10(12), 1423-1432. DOI: 10.1158/2326-6066.CIR-22-0366
Boelaars K, van Kooyk Y. Targeting myeloid cells for cancer immunotherapy: Siglec-7/9/10/15 and their ligands. Trends in Cancer. 2024, 10(3), 230-241. DOI: 10.1016/j.trecan.2023.11.009
Qiu H, Shao ZY, Wen X, Liu ZY, Chen ZQ, Qu DB, et al. Efferocytosis: An accomplice of cancer immune escape. Biomedicine & Pharmacotherapy. 2023, 167, 115540. DOI: 10.1016/j.biopha.2023.115540
Astuti Y, Raymant M, Quaranta V, Clarke K, Abudula M, Smith O, et al. Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis. Nature Cancer. 2024, 5(5), 774-790. DOI: 10.1038/s43018-024-00731-2
Mariño KV, Cagnoni AJ, Croci DO, Rabinovich GA. Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nature Reviews. Drug Discovery. 2023, 22(4), 295-316. DOI: 10.1038/s41573-023-00636-2
Wang ZL, Li N, Kong XX, Tao JP, Zhi Yang, Zhu H. Detection of tumor immune checkpoints: From pathological analysis to functional imaging. Holistic Integrative Oncology. 2025, 4, 76. DOI: 10.1007/s44178-025-00212-1
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Xuhui Chen, Haoran Yuan, Jia Shi, Guangdong Zeng, Xinjuan Fan, Yunlong Wang
This work is licensed under a Creative Commons Attribution 4.0 International License.
