Tumor exosomes in oncology: Role in tumor aggressiveness, invasion, metastasis and clinical implications
DOI:
https://doi.org/10.35954/SM2026.45.2.5.e401Keywords:
biomarkers tumor, liquid biopsy, neoplasms, exosomes, immune evasion, precision medicine, neoplasm metastasis, premetastatic niche, extracellular vesiclesAbstract
Introduction: Tumor exosomes have emerged as key mediators of intercellular communication in cancer, actively participating in multiple processes associated with tumor progression. These small extracellular vesicles, released by malignant cells and other components of the tumor microenvironment, transport proteins, lipids, DNA, and various types of RNA capable of modifying the behavior of recipient cells both in the local environment and in distant organs. A growing body of experimental evidence demonstrates that exosomes play a central role in tumor aggressiveness by promoting epithelial-mesenchymal transition, extracellular matrix remodeling, angiogenesis, therapeutic resistance, and immune evasion. They actively participate in the formation of the premetastatic niche, promoting the reprogramming of recipient tissues prior to the arrival of circulating tumor cells. The identification of exosomal integrins, microRNAs, and immunomodulatory proteins involved in metastatic organotropism has provided a deeper understanding of the mechanisms responsible for the systemic spread of cancer. Among these, the expression of exosomal PD-L1 represents a significant mechanism of immune evasion with the potential to impact the response to immunotherapies based on immune checkpoint inhibitors.
Objective: To critically analyze the role of tumor exosomes in tumor aggressiveness, local invasion, and metastasis formation, as well as to discuss their current and future clinical implications in precision oncology.
Discussion: From a translational perspective, exosomes represent a promising source of biomarkers for liquid biopsy due to the stability of their molecular content and their presence in various biological fluids. Furthermore, recent advances in extracellular vesicle proteomics and vesicle engineering technologies have expanded the possibilities for their use as diagnostic, prognostic, and therapeutic tools in the context of precision medicine. However, the clinical application of these findings remains limited by methodological challenges related to vesicular heterogeneity, a lack of standardization in isolation and characterization procedures, and the need for prospective, multicenter studies to validate their clinical utility. Taken together, exosomes represent key components of tumor biology and constitute an emerging platform with the potential to transform the diagnosis, monitoring, and treatment of cancer.
Conclusions: The available experimental evidence shows that exosomes play a decisive role in tumor aggressiveness by reprogramming stromal and immune cells, promoting the epithelial-mesenchymal transition, and preparing recipient tissues for metastatic colonization.
ACCEPTANCE NOTE: This article was approved by the Editorial Board.
Received for review: February 2026.
Accepted for publication: April 2026.
Publication date: July 2026.
Correspondence: Mataojo 2055. ZIP Code 11400. Tel: +598 299472572. Montevideo, Uruguay.
Contact email: pcabralc7@gmail.com
Downloads
References
World Health Organization. Global Health Estimates 2020: Deaths by Cause, Age, Sex, by Country and by Region, 2000–2019. Geneva: World Health Organization, 2020.
Brown JS, Amend SR, Austin RH, Gatenby RA, Hammarlund EU, Pienta KJ. Updating the definition of cancer. Mol Cancer Res. 2023; 21(11):1142-1147. https://doi.org/10.1158/1541-7786.MCR-23-0411 DOI: https://doi.org/10.1158/1541-7786.MCR-23-0411
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation Cell. 2011; 144(5):646-674. https://doi.org/10.1016/j.cell.2011.02.013 DOI: https://doi.org/10.1016/j.cell.2011.02.013
Hanahan D. Hallmarks of cancer: New dimensions. Cancer Discov. 2022; 12(1):31-46. https://doi.org/10.1158/2159-8290.CD-21-1059 DOI: https://doi.org/10.1158/2159-8290.CD-21-1059
Su J, Song Y, Zhu Z, Huang X, Fan J, Qiao J, Mao F. Cell-cell communication: new insights and clinical implications. Signal Transduct Target Ther. 2024; 9(1):196. https://doi.org/10.1038/s41392-024-01888-z DOI: https://doi.org/10.1038/s41392-024-01888-z
Polyakova N, Kalashnikova M, Belyavsky A. Non-Classical intercellular communications: Basic mechanisms and roles in biology and medicine. Int J Mol Sci. 2023; 24(7):6455. https://doi.org/10.3390/ijms24076455 DOI: https://doi.org/10.3390/ijms24076455
Gregory CD, Rimmer MP. Extracellular vesicles arising from apoptosis: forms, functions, and applications. J Pathol. 2023; 260(5):592-608. https://doi.org/10.1002/path.6138 DOI: https://doi.org/10.1002/path.6138
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996; 183(3):1161-1172. https://doi.org/10.1084/jem.183.3.1161 DOI: https://doi.org/10.1084/jem.183.3.1161
Welsh JA, Goberdhan DC, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, Cai, H, Di Vizio D, Driedonks TAP, Erdbrügger U, Falcon-Perez JM, Fu QL, Hill AF, Lenassi M, Lim SK, Mahoney MG, Mohanty S, Möller A, Nieuwland R, Ochiya T, Witwer KW. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. 2024; 13(2):e12404. https://doi.org/10.1002/jev2.12404 DOI: https://doi.org/10.1002/jev2.12404
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Zuba-Surma EK. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018; 7(1):1535750. https://doi.org/10.1080/20013078.2018.1535750 DOI: https://doi.org/10.1080/20013078.2018.1535750
Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT, Carter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature cell biology 2008; 10(12):1470-1476. https://doi.org/10.1038/ncb1800 DOI: https://doi.org/10.1038/ncb1800
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science (New York, N.Y.) 2020; 367(6478):eaau6977. https://doi.org/10.1126/science.aau6977 DOI: https://doi.org/10.1126/science.aau6977
Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019; 88:487-514. https://doi.org/10.1146/annurev-biochem-013118-111902 DOI: https://doi.org/10.1146/annurev-biochem-013118-111902
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Lyden D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature 2015; 527(7578):329-335. https://doi.org/10.1038/nature15756 DOI: https://doi.org/10.1038/nature15756
Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y, Bissell MJ, Cox TR, Giaccia AJ, Erler JT, Hiratsuka S, Ghajar CM, Lyden D. Pre-metastatic niches: organ-specific homes for metastases. Nature reviews. Cancer 2017; 17(5):302-317. https://doi.org/10.1038/nrc.2017.6 DOI: https://doi.org/10.1038/nrc.2017.6
Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis. Cancer Cell. 2016; 30(6):836-848. https://doi.org/10.1016/j.ccell.2016.10.009 DOI: https://doi.org/10.1016/j.ccell.2016.10.009
Yu D, Li Y, Wang M, Gu J, Xu W, Cai H, Fang X, Zhang X. Exosomes as a new frontier of cancer liquid biopsy. Molecular Cancer 2022; 21(1):56. https://doi.org/10.1186/s12943-022-01509-9 DOI: https://doi.org/10.1186/s12943-022-01509-9
Abels ER, Breakefield XO. Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell Mol Neurobiol. 2016; 36(3):301-312. https://doi.org/10.1007/s10571-016-0366-z DOI: https://doi.org/10.1007/s10571-016-0366-z
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013; 200(4):373-383. https://doi.org/10.1083/jcb.201211138 DOI: https://doi.org/10.1083/jcb.201211138
Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014; 3:24641. https://doi.org/10.3402/jev.v3.24641 DOI: https://doi.org/10.3402/jev.v3.24641
Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10(5):619-624. https://doi.org/10.1038/ncb1725 DOI: https://doi.org/10.1038/ncb1725
Paskeh MDA, Entezari M, Mirzaei S, Zabolian A, Saleki H, Naghdi MJ, et al. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol. 2022; 15(1):83. https://doi.org/10.1186/s13045-022-01305-4 DOI: https://doi.org/10.1186/s13045-022-01305-4
Kalluri R, McAndrews KM. The role of extracellular vesicles in cancer. Cell. 2023; 86(8):1610-1626. https://doi.org/10.1016/j.cell.2023.03.010 DOI: https://doi.org/10.1016/j.cell.2023.03.010
Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013; 91(4):431-437. https://doi.org/10.1007/s00109-013-1020-6 DOI: https://doi.org/10.1007/s00109-013-1020-6
Yang E, Wang X, Gong Z, Yu M, Wu H, Zhang D. Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression. Signal Transduct Target Ther. 2020; 5(1):242. https://doi.org/10.1038/s41392-020-00359-5 DOI: https://doi.org/10.1038/s41392-020-00359-5
Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010; 70(23):9621-30. https://doi.org/10.1158/0008-5472.CAN-10-1722 DOI: https://doi.org/10.1158/0008-5472.CAN-10-1722
Li W, Zhang X, Wang J, Li M, Cao C, Tan J, et al. TGFβ1 in fibroblasts-derived exosomes promotes epithelial-mesenchymal transition of ovarian cancer cells. Oncotarget. 2017; 8(56):96035-47. https://doi.org/10.18632/oncotarget.21635 DOI: https://doi.org/10.18632/oncotarget.21635
Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012; 18(6):883–91. https://doi.org/10.1038/nm.2753 DOI: https://doi.org/10.1038/nm.2753
Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-Mediated Metastasis: Communication from a Distance. Dev Cell. 2019; 49(3):347–360. https://doi.org/10.1016/j.devcel.2019.04.011 DOI: https://doi.org/10.1016/j.devcel.2019.04.011
Whiteside TL. Exosomes and tumor-mediated immune suppression. J Clin Invest. 2016; 126(4):1216–23. https://doi.org/10.1172/JCI81136 DOI: https://doi.org/10.1172/JCI81136
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018; 560(7718):382-386. https://doi.org/10.1038/s41586-018-0392-8 DOI: https://doi.org/10.1038/s41586-018-0392-8
Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang U, Qi F, Fong L, Blelloch R. Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory. Cell. 2019; 177(2):414–427.e13. https://doi.org/10.1016/j.cell.2019.02.016 DOI: https://doi.org/10.1016/j.cell.2019.02.016
Ricklefs FL, Alayo Q, Krenzlin H, Mahmoud AB, Speranza MC, Nakashima H, et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv. 2018; 4(3):eaar2766. https://doi.org/10.1126/sciadv.aar2766 DOI: https://doi.org/10.1126/sciadv.aar2766
Guo Y, Ji X, Liu J, Fan D, Zhou Q, Chen C, Wang W, Wang G, Wang H, Yuan W, Ji Z, Sun Z. Effects of exosomes on pre-metastatic niche formation in tumors. Mol Cancer. 2019; 18(1):39. https://doi.org/10.1186/s12943-019-0995-1 DOI: https://doi.org/10.1186/s12943-019-0995-1
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015; 17(6):8168226. https://doi.org/10.1038/ncb3169 DOI: https://doi.org/10.1038/ncb3169
Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014; 25(4):501-515. https://doi.org/10.1016/j.ccr.2014.03.007 DOI: https://doi.org/10.1016/j.ccr.2014.03.007
Tan S, Yang Y, Yang W, Han Y, Huang L, Yang R, et al. Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment. J Exp Clin Cancer Res. 2023; 42(1):59. https://doi.org/10.1186/s13046-023-02634-z DOI: https://doi.org/10.1186/s13046-023-02634-z
Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011; 71(11):3792-3801. https://doi.org/10.1158/0008-5472.CAN-10-4455 DOI: https://doi.org/10.1158/0008-5472.CAN-10-4455
Plebanek MP, Angeloni NL, Vinokour E, Li J, Henkin A, Martinez-Marin D, et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat Commun. 2017;8(1):1319. https://doi.org/10.1038/s41467-017-01433-3 DOI: https://doi.org/10.1038/s41467-017-01433-3
Barile L, Vassalli G. Exosomes: Therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017; 174:63-78. https://doi.org/10.1016/j.pharmthera.2017.02.020 DOI: https://doi.org/10.1016/j.pharmthera.2017.02.020
Wang X, Tian L, Lu J, Ng IO. Exosomes and cancer - Diagnostic and prognostic biomarkers and therapeutic vehicle. Oncogenesis. 2022; 11(1):54. https://doi.org/:10.1038/s41389-022-00431-5 DOI: https://doi.org/10.1038/s41389-022-00431-5
Machida T, Tomofuji T, Maruyama T, Yoneda T, Ekuni D, Azuma T, Miyai H, Mizuno H, Kato H, Tsutsumi K, Uchida D, Takaki A, Okada H, Morita M. miR 1246 and miR 4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer. Oncol Rep. 2016; 36(4):2375-2381. https://doi.org/10.3892/or.2016.5021 DOI: https://doi.org/10.3892/or.2016.5021
Casanova-Salas I, Aguilar D, Cordoba-Terreros S, Agundez L, Brandariz J, Herranz N, et al. Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution. Cancer Cell. 2024;42(7):1301–12.e7. https://doi.org/10.1016/j.ccell.2024.06.003 DOI: https://doi.org/10.1016/j.ccell.2024.06.003
Arafa AT, Boytim E, Ludwig ML, Kollitz L, Yang T, Storey KM, et al. Plasma extracellular vesicle proteomics nominates candidate biomarkers of 177Lu-PSMA-617 outcomes in metastatic prostate cancer patients. Cell Rep Med. 2026; 7(5):102764. https://doi.org/10.1016/j.xcrm.2026.102764 DOI: https://doi.org/10.1016/j.xcrm.2026.102764
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29(4):341-345. https://doi.org/10.1038/nbt.1807 DOI: https://doi.org/10.1038/nbt.1807
Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019; 9:19. https://doi.org/10.1186/s13578-019-0282-2 DOI: https://doi.org/10.1186/s13578-019-0282-2
Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV, Batrakova EV. Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release. 2015; 207:18-30. https://doi.org/10.1016/j.jconrel.2015.03.033 DOI: https://doi.org/10.1016/j.jconrel.2015.03.033
Silva LHA, Silva SM, Lima ECD, Silva RC, Weiss DJ, Morales MM, Cruz F, Rocco PRM. Effects of static magnetic fields on natural or magnetized mesenchymal stromal cells: Repercussions for magnetic targeting. Nanomedicine 2018; 14(7):2075-2085. https://doi.org/10.1016/j.nano.2018.06.002 DOI: https://doi.org/10.1016/j.nano.2018.06.002
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 : Ximena Camacho, Leticia Venerando y Pablo Cabral.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Until 2024 we use the Creative Commons Attribution/NonCommercial Attribution 4.0 International License https://creativecommons.org/licenses/by-nc/4.0/deed.es. Which states that: you are free to share, copy and redistribute the material in any medium or format, as well as to adapt, remix, transform and build upon the material. Under the following terms:
Attribution: you must give proper credit , provide a link to the license, and indicate if changes have been made . You may do so in any reasonable manner, but not in such a way as to suggest that you or your use is endorsed by the licensor.
NonCommercial: you may not use the material for commercial purposes.
As of 2025 authors retain their copyright and assign to the journal the right of first publication of their work, which shall simultaneously be subject to the license https://creativecommons.org/licenses/by-nc-sa/4.0/deed.es that permits sharing, copying and redistribution of the material in any medium or format provided that initial publication in this journal is indicated. Adapt, remix, transform and build upon the material. If you remix, transform, or build from the material, you must distribute your contribution under the same license as the original and may not make use of the material for commercial purposes.
Under the following terms:
1. Attribution: you must give proper credit, provide a link to the license, and indicate whether changes have been made. You may do so in any reasonable manner, but not in such a way as to suggest that you or your use is endorsed by the licensor.
2. NonCommercial: you may not use the material for commercial purposes.
3. ShareAlike: if you remix, transform or build upon the material, you must distribute your contribution under the same license as the original.
PlumX Metrics
