Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both tumor and stromal cells, carry a diverse cargo of proteins, nucleic acids, and lipids, reflecting the dynamic cellular landscape and mediating intricate interactions between cells. This review provides a comprehensive overview of the biogenesis, composition, and functional roles of EVs in cancer, highlighting their significance in both basic research and clinical applications. We discuss how cancer cells manipulate EV biogenesis pathways to produce vesicles enriched with pro-tumorigenic molecules, explore the specific contributions of EVs to key hallmarks of cancer, such as angiogenesis, metastasis, and immune evasion, emphasizing their role in shaping TME and driving therapeutic resistance. Concurrently, we submit recent knowledge on how the cargo of EVs can serve as a valuable source of biomarkers for minimally invasive liquid biopsies, and its therapeutic potential, particularly as targeted drug delivery vehicles and immunomodulatory agents, showcasing their promise for enhancing the efficacy and safety of cancer treatments. By deciphering the intricate messages carried by EVs, we can gain a deeper understanding of cancer biology and develop more effective strategies for early detection, targeted therapy, and immunotherapy, paving the way for a new era of personalized and precise cancer medicine with the potential to significantly improve patient outcomes.

Centre for Nanomaterials and Biotechnology Faculty of Science Jan Evangelista Purkyně University in Ústí Nad Labem Pasteurova 3632 15 Ústí Nad Labem 40096 Czech Republic

Core Facilities Department of Research and Diagnostics IRCCS Istituto Giannina Gaslini 16147 Genoa Italy

Institute of Photonics and Electronics of the CAS Chaberská 1014 57 Prague 182 51 Czech Republic

Laboratory of Experimental Therapies in Oncology IRCCS Istituto Giannina Gaslini Via G Gaslini 5 16147 Genoa Italy

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Berumen Sánchez G, et al. Extracellular vesicles: mediators of intercellular communication in tissue injury and disease. Cell Commun Signaling. 2021;19(1):104. PubMed PMC

Hoshino A, et al. Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. Cell. 2020;182(4):1044-1061.e18. PubMed PMC

Kumar MA, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther. 2024;9(1):27. PubMed PMC

Belov L, et al. Extensive surface protein profiles of extracellular vesicles from cancer cells may provide diagnostic signatures from blood samples. J Extracellular Vesicles. 2016;5(1):25355. PubMed PMC

Ilamathi HS, El Andaloussi, Wiklander OPB. Targeted tumor delivery using extracellular vesicles. In: Ü. Langel, editor. Cancer-targeted drug delivery. New York: Springer; 2025. p. 125–153.

Couch Y, et al. A brief history of nearly EV-erything - The rise and rise of extracellular vesicles. J Extracell Vesicles. 2021;10(14):e12144. PubMed PMC

Lötvall J, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3(1):26913. PubMed PMC

Théry C, et al. 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. PubMed PMC

Welsh JA, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. 2024;13(2):e12404. PubMed PMC

Zhang Q, et al. Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets. Nat Cell Biol. 2021;23(12):1240–54. PubMed PMC

Dixson AC, et al. Context-specific regulation of extracellular vesicle biogenesis and cargo selection. Nat Rev Mol Cell Biol. 2023;24(7):454–76. PubMed PMC

Anand S, Samuel M, Mathivanan S. Exomeres: A New Member of Extracellular Vesicles Family. Subcell Biochem. 2021;97:89–97. PubMed

Logozzi M, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE. 2009;4(4):e5219. PubMed PMC

Riches A, et al. Regulation of exosome release from mammary epithelial and breast cancer cells - a new regulatory pathway. Eur J Cancer. 2014;50(5):1025–34. PubMed

Kharmate G, et al. Epidermal Growth Factor Receptor in Prostate Cancer Derived Exosomes. PLoS ONE. 2016;11(5):e0154967. PubMed PMC

Fan SJ, et al. Glutamine deprivation alters the origin and function of cancer cell exosomes. Embo J. 2020;39(16):e103009. PubMed PMC

Bebelman MP, et al. The forces driving cancer extracellular vesicle secretion. Neoplasia. 2021;23(1):149–57. PubMed PMC

Bebelman MP, et al. Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther. 2018;188:1–11. PubMed

Willms E, et al. Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression. Front Immunol. 2018;9:738. PubMed PMC

Menck K, et al. Microvesicles in Cancer: Small Size, Large Potential. Int J Mol Sci. 2020;21(15):5373. PubMed PMC

Gulati, R., et al., Exosomes as Theranostic Targets: Implications for the Clinical Prognosis of Aggressive Cancers. Frontiers in Molecular Biosciences, 2022. 9. PubMed PMC

Blanc L, Vidal M. New insights into the function of Rab GTPases in the context of exosomal secretion. Small GTPases. 2018;9(1–2):95–106. PubMed PMC

Li Z, et al. Functional implications of Rab27 GTPases in Cancer. Cell Commun Signal. 2018;16(1):44. PubMed PMC

Wen H, et al. MiR-185-5p targets RAB35 gene to regulate tumor cell-derived exosomes-mediated proliferation, migration and invasion of non-small cell lung cancer cells. Aging (Albany NY). 2021;13(17):21435–50. PubMed PMC

Villagomez FR, et al. The role of the oncogenic Rab35 in cancer invasion, metastasis, and immune evasion, especially in leukemia. Small GTPases. 2020;11(5):334–45. PubMed PMC

Alam MR, Rahman MM, Li Z. The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy. Genes Dis. 2024;11(1):321–34. PubMed PMC

Liu C, et al. Identification of the SNARE complex that mediates the fusion of multivesicular bodies with the plasma membrane in exosome secretion. J Extracell Vesicles. 2023;12(9):e12356. PubMed PMC

Mitani F, et al. SNAP23-Mediated perturbation of cholesterol-enriched membrane microdomain promotes extracellular vesicle production in Src-activated cancer cells. Biol Pharm Bull. 2022;45(10):1572–80. PubMed

Ferraiuolo RM, et al. The Multifaceted Roles of the Tumor Susceptibility Gene 101 (TSG101) in Normal Development and Disease. Cancers (Basel). 2020;12(2):450. PubMed PMC

Keeley O, Coyne AN. Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease. Nucleus. 2024;15(1):2349085. PubMed PMC

Liu F, et al. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Mol Cancer. 2024;23(1):148. PubMed PMC

Hánělová K, et al. Protein cargo in extracellular vesicles as the key mediator in the progression of cancer. Cell Commun Signaling. 2024;22(1):25. PubMed PMC

Lee YJ, et al. GPR143 controls ESCRT-dependent exosome biogenesis and promotes cancer metastasis. Dev Cell. 2023;58(4):320-334.e8. PubMed

Hoshino D, et al. Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep. 2013;5(5):1159–68. PubMed PMC

Peng X, et al. LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation. J Exp Clin Cancer Res. 2021;40(1):183. PubMed PMC

Lai H, et al. exoRBase 2.0: an atlas of mRNA, lncRNA and circRNA in extracellular vesicles from human biofluids. Nucleic Acids Research. 2021;50(D1):D118–28. PubMed PMC

Han Z, et al. Circular RNAs and Their Role in Exosomes. Front Oncol. 2022;12:848341. PubMed PMC

Vu LT, et al. microRNA exchange via extracellular vesicles in cancer. Cell Prolif. 2020;53(11):e12877. PubMed PMC

Wang K, et al. Identification of the microRNA alterations in extracellular vesicles derived from human haemorrhoids. Exp Physiol. 2023;108(5):752–61. PubMed PMC

Dhar R, et al. Interrelation between extracellular vesicles miRNAs with chronic lung diseases. J Cell Physiol. 2022;237(11):4021–36. PubMed

Weng Q, et al. Extracellular vesicles-associated tRNA-derived fragments (tRFs): biogenesis, biological functions, and their role as potential biomarkers in human diseases. J Mol Med. 2022;100(5):679–95. PubMed PMC

Koeppen K, Hampton TH, Barnaby R, Roche C, Gerber SA, Goo YA, et al. An rRNA fragment in extracellular vesicles secreted by human airway epithelial cells increases the fluoroquinolone sensitivity of P. aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2023;325(1):L54–l65. PubMed PMC

James V, et al. Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo. Stem Cells Dev. 2021;30(24):1215–27. PubMed PMC

Li B, et al. piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment. Oncogene. 2019;38(26):5227–38. PubMed

Driedonks TAP, Nolte-’t Hoen ENM. Circulating Y-RNAs in Extracellular Vesicles and Ribonucleoprotein Complexes; Implications for the Immune System. Front Immunol. 2019;9:3164. PubMed PMC

Chen T-Y, et al. Extracellular vesicles carry distinct proteo-transcriptomic signatures that are different from their cancer cell of origin. iScience. 2022;25(6):104414. PubMed PMC

Sharma A. Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology. J Cell Physiol. 2023;238(4):687–97. PubMed

Strzyz P. Alternative to lysosomal degradation: mitochondrial removal via EVs. Nat Rev Mol Cell Biol. 2023;24(11):776–776. PubMed

Ding Y, et al. Emerging degrader technologies engaging lysosomal pathways. Chem Soc Rev. 2022;51(21):8832–76. PubMed PMC

Li G, Marlin MC. Rab Family of GTPases. In: Li G., editor. Rab GTPases: Methods and protocols. New York: Springer; 2015. p. 1–15. PubMed PMC

Martins B, et al. Contribution of extracellular vesicles for the pathogenesis of retinal diseases: shedding light on blood-retinal barrier dysfunction. J Biomed Sci. 2024;31(1):48. PubMed PMC

Sun Y, Zhang M, Ge L. A RAB transition orchestrates membrane trafficking in unconventional protein secretion. J Cell Biol. 2024;223(2):e202312096. PubMed PMC

Xu S, et al. Function and regulation of Rab GTPases in cancers. Cell Biol Toxicol. 2024;40(1):28. PubMed PMC

Thomas JD, et al. Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell. 2014;26(5):754–69. PubMed PMC

Wheeler DB, et al. Identification of an oncogenic RAB protein. Science. 2015;350(6257):211–7. PubMed PMC

Gopal Krishnan PD, et al. Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer. Cancers. 2020;12(2):259. PubMed PMC

Pellinen T, et al. Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of beta1-integrins. J Cell Biol. 2006;173(5):767–80. PubMed PMC

Caswell PT, et al. Rab25 Associates with α5β1 Integrin to Promote Invasive Migration in 3D Microenvironments. Dev Cell. 2007;13(4):496–510. PubMed

Margiotta A, et al. Rab7a regulates cell migration through Rac1 and vimentin. Biochim Biophys Acta Mol Cell Res. 2017;1864(2):367–81. PubMed

AN, H.J., et al., <em>RAB27A</em> and <em>RAB27B</em> Expression May Predict Lymph Node Metastasis and Survival in Patients With Gastric Cancer. Cancer Genom Proteom. 2022;19(5):606–613. PubMed PMC

NAMBARA S, et al. Rab27b, a regulator of exosome secretion, is associated with peritoneal metastases in gastric cancer. Cancer Genom Proteom. 2023;20(1):30–39. PubMed PMC

Song DH, et al. Exosome-mediated secretion of miR-127-3p regulated by RAB27A accelerates metastasis in renal cell carcinoma. Cancer Cell Int. 2024;24(1):153. PubMed PMC

Kaur M, et al. Most recent advances and applications of extracellular vesicles in tackling neurological challenges. Med Res Rev. 2024;44(4):1923–66. PubMed

van der Borg G, et al. SNARE mimic peptide triggered membrane fusion kinetics revealed using single particle techniques. Phys Chem Chem Phys. 2023;25(18):13019–26. PubMed

Li Y, et al. Pan-cancer proteogenomics connects oncogenic drivers to functional states. Cell. 2023;186(18):3921-3944.e25. PubMed

Peak TC, et al. Syntaxin 6-mediated exosome secretion regulates enzalutamide resistance in prostate cancer. Mol Carcinog. 2020;59(1):62–72. PubMed PMC

Yang L, et al. Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma. Mol Cancer. 2019;18(1):78. PubMed PMC

Qin W, et al. Long non-coding RNA HOTAIR promotes tumorigenesis and forecasts a poor prognosis in cholangiocarcinoma. Sci Rep. 2018;8(1):12176. PubMed PMC

Williams KC, Coppolino MG. SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion. J Cell Sci. 2014;127(8):1712–25. PubMed

Miyata T, et al. Involvement of syntaxin 4 in the transport of membrane-type 1 matrix metalloproteinase to the plasma membrane in human gastric epithelial cells. Biochem Biophys Res Commun. 2004;323(1):118–24. PubMed

Williams KC, Coppolino MG. Phosphorylation of membrane type 1-matrix metalloproteinase (MT1-MMP) and its vesicle-associated membrane protein 7 (VAMP7)-dependent trafficking facilitate cell invasion and migration. J Biol Chem. 2011;286(50):43405–16. PubMed PMC

Williams KC, McNeilly RE, Coppolino MG. SNAP23, Syntaxin4, and vesicle-associated membrane protein 7 (VAMP7) mediate trafficking of membrane type 1-matrix metalloproteinase (MT1-MMP) during invadopodium formation and tumor cell invasion. Mol Biol Cell. 2014;25(13):2061–70. PubMed PMC

Day P, et al. Syntaxins 3 and 4 mediate vesicular trafficking of α5β1 and α3β1 integrins and cancer cell migration. Int J Oncol. 2011;39(4):863–71. PubMed

Camarena ME, et al. Microproteins encoded by noncanonical ORFs are a major source of tumor-specific antigens in a liver cancer patient meta-cohort. Sci Adv. 2024;10(28):eadn3628. PubMed PMC

Rahmati S, Moeinafshar A, Rezaei N. The multifaceted role of extracellular vesicles (EVs) in colorectal cancer: metastasis, immune suppression, therapy resistance, and autophagy crosstalk. J Transl Med. 2024;22(1):452. PubMed PMC

Ying H, et al. Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc Natl Acad Sci. 2010;107(15):6912–7. PubMed PMC

Catalano M, O’Driscoll L. Inhibiting extracellular vesicles formation and release: a review of EV inhibitors. J Extracell Vesicles. 2020;9(1):1703244. PubMed PMC

Zhu P-J, et al. Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability. J Med Chem. 2021;64(15):11330–53. PubMed

Tron AE, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9(1):5341. PubMed PMC

Han JM, Kim HL, Jung HJ. Ampelopsin Inhibits Cell Proliferation and Induces Apoptosis in HL60 and K562 Leukemia Cells by Downregulating AKT and NF-κB Signaling Pathways. Int J Mol Sci. 2021;22(8):4265. PubMed PMC

Anaya-Eugenio GD, et al. A pentamethoxylated flavone from Glycosmis ovoidea promotes apoptosis through the intrinsic pathway and inhibits migration of MCF-7 breast cancer cells. Phytother Res. 2021;35(3):1634–45. PubMed PMC

Shin M-K, et al. In Vivo and In Vitro Effects of Tracheloside on Colorectal Cancer Cell Proliferation and Metastasis. Antioxidants. 2021;10(4):513. PubMed PMC

Lin C-Y, et al. Membrane protein-regulated networks across human cancers. Nat Commun. 2019;10(1):3131. PubMed PMC

Nazari SS, et al. Long Prehensile Protrusions Can Facilitate Cancer Cell Invasion through the Basement Membrane. Cells. 2023;12(20):2474. PubMed PMC

Pratiwi L, Elisa E, Sutanto H. Probing the protrusions: lamellipodia and filopodia in cancer invasion and beyond. Mechanobiol Med. 2024;2(2):100064.

Hu HT, et al. The cellular protrusions for inter-cellular material transfer: similarities between filopodia, cytonemes, tunneling nanotubes, viruses, and extracellular vesicles. Front Cell Dev Biol. 2024;12:1422227. PubMed PMC

Zhu X, et al. Macrophages release IL11-containing filopodial tip vesicles and contribute to renal interstitial inflammation. Cell Commun Signaling. 2023;21(1):293. PubMed PMC

Gerke V, et al. Annexins—a family of proteins with distinctive tastes for cell signaling and membrane dynamics. Nat Commun. 2024;15(1):1574. PubMed PMC

Zhang C, et al. Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance. Mol Cancer. 2024;23(1):18. PubMed PMC

Lane J, et al. Structure and role of WASP and WAVE in Rho GTPase signalling in cancer. Cancer Genomics Proteomics. 2014;11(3):155–65. PubMed

Rana PS, et al. The Role of WAVE2 Signaling in Cancer. Biomedicines. 2021;9(9):1217. PubMed PMC

Ayanlaja AA, et al. Susceptibility of cytoskeletal-associated proteins for tumor progression. Cell Mol Life Sci. 2021;79(1):13. PubMed PMC

Cao Z, et al. Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects. J Biomed Sci. 2025;32(1):7. PubMed PMC

Nedaeinia R, et al. The role of cancer-associated fibroblasts and exosomal miRNAs-mediated intercellular communication in the tumor microenvironment and the biology of carcinogenesis: a systematic review. Cell Death Discovery. 2024;10(1):380. PubMed PMC

Yu L, et al. Apoptotic bodies: bioactive treasure left behind by the dying cells with robust diagnostic and therapeutic application potentials. J Nanobiotechnol. 2023;21(1):218. PubMed PMC

Zou X, et al. Advances in biological functions and applications of apoptotic vesicles. Cell Commun Signaling. 2023;21(1):260. PubMed PMC

Driscoll MK, et al. Proteolysis-free amoeboid migration of melanoma cells through crowded environments via bleb-driven worrying. Dev Cell. 2024;59(18):2414-2428.e8. PubMed PMC

Reichman-Fried M, Raz E. Bleb protrusions help cancer cells to cheat death. Nature. 2023;615(7952):402–3. PubMed

Najafi S, Majidpoor J, Mortezaee K. Extracellular vesicle–based drug delivery in cancer immunotherapy. Drug Deliv Transl Res. 2023;13(11):2790–806. PubMed PMC

Wen J, et al. Comparison of immunotherapy mediated by apoptotic bodies, microvesicles and exosomes: apoptotic bodies’ unique anti-inflammatory potential. J Transl Med. 2023;21(1):478. PubMed PMC

Sullivan R, et al. The Emerging Roles of Extracellular Vesicles As Communication Vehicles within the Tumor Microenvironment and Beyond. Front Endocrinol. 2017;8:194. PubMed PMC

Fu Y, Xiong S. Differential traits between microvesicles and exosomes in enterovirus infection. MedComm. 2023;4(5):e384. PubMed PMC

Andreola G, et al. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med. 2002;195(10):1303–16. PubMed PMC

Che SPY, Park JY, Stokol T. Tissue Factor-Expressing Tumor-Derived Extracellular Vesicles Activate Quiescent Endothelial Cells via Protease-Activated Receptor-1. Front Oncol. 2017;7:261. PubMed PMC

Hoshino A, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35. PubMed PMC

Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol. 2015;40:41–51. PubMed PMC

Xiang X, et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer. 2009;124(11):2621–33. PubMed PMC

Yu D, et al. Exosomes as a new frontier of cancer liquid biopsy. Mol Cancer. 2022;21(1):56. PubMed PMC

Risha Y, et al. The proteomic analysis of breast cell line exosomes reveals disease patterns and potential biomarkers. Sci Rep. 2020;10(1):13572. PubMed PMC

Esfandyari S, et al. Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy. Int J Mol Sci. 2021;22(4):2165. PubMed PMC

Chanteloup G, et al. Membrane-bound exosomal HSP70 as a biomarker for detection and monitoring of malignant solid tumours: a pilot study. Pilot and Feasibility Studies. 2020;6(1):35. PubMed PMC

Wu S, et al. Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer. Mol Cancer. 2021;20(1):17. PubMed PMC

Fan Y, et al. High-sensitive and multiplex biosensing assay of NSCLC-derived exosomes via different recognition sites based on SPRi array. Biosens Bioelectron. 2020;154:112066. PubMed

Wang Y-T, et al. Proteomic Analysis of Exosomes for Discovery of Protein Biomarkers for Prostate and Bladder Cancer. Cancers. 2020;12(9):2335. PubMed PMC

Yang ZJ, et al. Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43. Int J Med Sci. 2022;19(7):1205–15. PubMed PMC

Kartikasari AER, et al. Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis. Front Oncol. 2021;11:692142. PubMed PMC

Liu T, et al. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2(1):17023. PubMed PMC

Markopoulos GS, et al. Roles of NF-κB Signaling in the Regulation of miRNAs Impacting on Inflammation in Cancer. Biomedicines. 2018;6(2):40. PubMed PMC

Aslan C, et al. Tumor-derived exosomes: Implication in angiogenesis and antiangiogenesis cancer therapy. J Cell Physiol. 2019;234(10):16885–903. PubMed

Ahmadi M, Rezaie J. Tumor cells derived-exosomes as angiogenenic agents: possible therapeutic implications. J Transl Med. 2020;18(1):249. PubMed PMC

Du E, et al. The critical role of the interplays of EphrinB2/EphB4 and VEGF in the induction of angiogenesis. Mol Biol Rep. 2020;47(6):4681–90. PubMed

Bhat A, et al. Exosomes from cervical cancer cells facilitate pro-angiogenic endothelial reconditioning through transfer of Hedgehog–GLI signaling components. Cancer Cell Int. 2021;21(1):319. PubMed PMC

Feng Q, et al. A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis. Nat Commun. 2017;8(1):14450. PubMed PMC

Zhang S, Yang J, Shen L. Extracellular vesicle-mediated regulation of tumor angiogenesis— implications for anti-angiogenesis therapy. J Cell Mol Med. 2021;25(6):2776–85. PubMed PMC

Wang X, et al. The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer. Exp Mol Med. 2022;54(9):1390–400. PubMed PMC

Tang H, et al. HSP90/IKK-rich small extracellular vesicles activate pro-angiogenic melanoma-associated fibroblasts via the NF-κB/CXCL1 axis. Cancer Sci. 2022;113(4):1168–81. PubMed PMC

van den Brûle FA, et al. Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression. Int J Cancer. 2000;89(4):361–7. PubMed

Califice S, et al. Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3. Oncogene. 2004;23(45):7527–36. PubMed

Mehul B, Hughes RC. Plasma membrane targetting, vesicular budding and release of galectin 3 from the cytoplasm of mammalian cells during secretion. J Cell Sci. 1997;110(Pt 10):1169–78. PubMed

Guo Y, et al. Effects of exosomes on pre-metastatic niche formation in tumors. Mol Cancer. 2019;18(1):39. PubMed PMC

Maji S, et al. Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis. Mol Cancer Res. 2017;15(1):93–105. PubMed PMC

Chaudhary P, et al. Serum exosomal-annexin A2 is associated with African-American triple-negative breast cancer and promotes angiogenesis. Breast Cancer Res. 2020;22(1):11. PubMed PMC

Huang Z, et al. Exosomes Derived from Hypoxic Colorectal Cancer Cells Transfer Wnt4 to Normoxic Cells to Elicit a Prometastatic Phenotype. Int J Biol Sci. 2018;14(14):2094–102. PubMed PMC

Zhang W, et al. Small extracellular vesicles: from mediating cancer cell metastasis to therapeutic value in pancreatic cancer. Cell Commun Signaling. 2022;20(1):1. PubMed PMC

Shen T, et al. Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress. FASEB J. 2020;34(6):8442–58. PubMed

Li M, et al. Pancreatic stellate cells derived exosomal miR-5703 promotes pancreatic cancer by downregulating CMTM4 and activating PI3K/Akt pathway. Cancer Lett. 2020;490:20–30. PubMed

Cao W, et al. Hypoxic pancreatic stellate cell-derived exosomal mirnas promote proliferation and invasion of pancreatic cancer through the PTEN/AKT pathway. Aging (Albany NY). 2021;13(5):7120–32. PubMed PMC

Chiba M, et al. Exosomes released from pancreatic cancer cells enhance angiogenic activities via dynamin-dependent endocytosis in endothelial cells in vitro. Sci Rep. 2018;8(1):11972. PubMed PMC

Liu Z-L, et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. 2023;8(1):198. PubMed PMC

Lu R, et al. miR-338 modulates proliferation and autophagy by PI3K/AKT/mTOR signaling pathway in cervical cancer. Biomed Pharmacother. 2018;105:633–44. PubMed

Yu Y, et al. Hypoxia-induced exosomes promote hepatocellular carcinoma proliferation and metastasis via miR-1273f transfer. Exp Cell Res. 2019;385(1):111649. PubMed

Kucharzewska P, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci. 2013;110(18):7312–7. PubMed PMC

Aga M, et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33(37):4613–22. PubMed PMC

Ramteke A, et al. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 2015;54(7):554–65. PubMed PMC

Rong L, et al. Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells. Oncol Lett. 2016;11(1):500–4. PubMed PMC

Zhang X, et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer. 2019;18(1):40. PubMed PMC

Deep G, et al. Exosomes secreted by prostate cancer cells under hypoxia promote matrix metalloproteinases activity at pre-metastatic niches. Mol Carcinog. 2020;59(3):323–32. PubMed PMC

de Jong OG, et al. Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2. J Cell Mol Med. 2016;20(2):342–50. PubMed PMC

Erler JT, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006;440(7088):1222–6. PubMed

Li L, et al. Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype. Cancer Res. 2016;76(7):1770–80. PubMed

Hsu YL, et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36(34):4929–42. PubMed

Lin J, et al. Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1. J Hematol Oncol. 2022;15(1):128. PubMed PMC

Mezu-Ndubuisi OJ, Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr Res. 2021;89(7):1619–26. PubMed PMC

Valdembri D, Serini G. The roles of integrins in cancer. Fac Rev. 2021;10:45. PubMed PMC

Paolillo M, Schinelli S. Integrins and Exosomes, a Dangerous Liaison in Cancer Progression. Cancers. 2017;9(8):95. PubMed PMC

Tian W, Liu S, Li B. Potential Role of Exosomes in Cancer Metastasis. Biomed Res Int. 2019;2019(1):4649705. PubMed PMC

Costa-Silva B, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17(6):816–26. PubMed PMC

Pickarski M, et al. Orally active αvβ3 integrin inhibitor MK-0429 reduces melanoma metastasis. Oncol Rep. 2015;33(6):2737–45. PubMed PMC

Huang R, Rofstad EK. Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma. J Exp Clin Cancer Res. 2018;37(1):92. PubMed PMC

Mitra AK, et al. Ligand-independent activation of c-Met by fibronectin and α5β1-integrin regulates ovarian cancer invasion and metastasis. Oncogene. 2011;30(13):1566–76. PubMed PMC

Bartolomé RA, et al. VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers. Oncotarget. 2016;8(1):215–27. PubMed PMC

Giusti I, Dolo V. Extracellular Vesicles in Prostate Cancer: New Future Clinical Strategies? Biomed Res Int. 2014;2014(1):561571. PubMed PMC

Babiker AA, et al. Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin. Prostate. 2006;66(7):675–86. PubMed

Babiker AA, et al. Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attack. Prostate. 2005;62(2):105–14. PubMed

Zhang W, et al. The role of extracellular vesicle immune checkpoints in cancer. Clin Exp Immunol. 2024;216(3):230–9. PubMed PMC

Li Q, et al. Tumor-Derived Extracellular Vesicles: Their Role in Immune Cells and Immunotherapy. Int J Nanomedicine. 2021;16:5395–409. PubMed PMC

Huntington ND, Cursons J, Rautela J. The cancer–natural killer cell immunity cycle. Nat Rev Cancer. 2020;20(8):437–54. PubMed

Zhao J, et al. Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer. Cancers. 2019;11(6):874. PubMed PMC

Moloudizargari M, et al. Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity. Daru. 2020;28(2):647–59. PubMed PMC

Lazarova M, Steinle A. Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. Front Immunol. 2019;10:2689. PubMed PMC

Rouce RH, et al. The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. Leukemia. 2016;30(4):800–11. PubMed PMC

Szczepanski MJ, et al. Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica. 2011;96(9):1302–9. PubMed PMC

Clayton A, et al. Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol. 2008;180(11):7249–58. PubMed

Liu C, et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol. 2006;176(3):1375–85. PubMed

Chen J-H, et al. Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-α and perforin. J Zhejiang Univ-SCIENCE B. 2016;17(7):537–44. PubMed PMC

Angiari S, et al. Regulation of T cell activation and pathogenicity by dimeric pyruvate kinase M2 (PKM2). J Immunol. 2019;202(1_Supplement):125.11-125.11.

Czystowska-Kuzmicz M, et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat Commun. 2019;10(1):3000. PubMed PMC

Chang CH, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229–41. PubMed PMC

Ho PC, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217–28. PubMed PMC

Clayton A, et al. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol. 2011;187(2):676–83. PubMed

Burnstock G, Di Virgilio F. Purinergic signalling and cancer. Purinergic Signal. 2013;9(4):491–540. PubMed PMC

Ohta A, Sitkovsky M. Extracellular adenosine-mediated modulation of regulatory T cells. Front Immunol. 2014;5:304. PubMed PMC

Chennakrishnaiah S, et al. Leukocytes as a reservoir of circulating oncogenic DNA and regulatory targets of tumor-derived extracellular vesicles. J Thromb Haemost. 2018;16(9):1800–13. PubMed

Ye S-B, et al. Exosomal miR-24-3p impedes T-cell function by targeting and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol. 2016;240(3):329–40. PubMed

Zhou J, et al. Exosomes Released from Tumor-Associated Macrophages Transfer miRNAs That Induce a Treg/Th17 Cell Imbalance in Epithelial Ovarian Cancer. Cancer Immunol Res. 2018;6(12):1578–92. PubMed

Ye S-B, et al. Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget. 2014;5(14):5439–52. PubMed PMC

Daassi D, Mahoney KM, Freeman GJ. The importance of exosomal PDL1 in tumour immune evasion. Nat Rev Immunol. 2020;20(4):209–15. PubMed

Abusamra AJ, et al. Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis. 2005;35(2):169–73. PubMed

Clayton A, et al. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 2007;67(15):7458–66. PubMed

McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol. 2019;37:457–95. PubMed

Baitsch L, et al. Exhaustion of tumor-specific CD8⁺ T cells in metastases from melanoma patients. J Clin Invest. 2011;121(6):2350–60. PubMed PMC

Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9. PubMed

Yin C, et al. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. OncoImmunology. 2019;8(7):e1601479. PubMed PMC

Wang X, et al. 14-3-3ζ delivered by hepatocellular carcinoma-derived exosomes impaired anti-tumor function of tumor-infiltrating T lymphocytes. Cell Death Dis. 2018;9(2):159. PubMed PMC

Wang J, et al. circRNA-002178 act as a ceRNA to promote PDL1/PD1 expression in lung adenocarcinoma. Cell Death Dis. 2020;11(1):32. PubMed PMC

Wieckowski EU, et al. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol. 2009;183(6):3720–30. PubMed PMC

Groth C, et al. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer. 2019;120(1):16–25. PubMed PMC

Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108–19. PubMed PMC

Tian X, et al. Long Non-Coding RNA HOXA Transcript Antisense RNA Myeloid-Specific 1-HOXA1 Axis Downregulates the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in Lung Cancer. Front Immunol. 2018;9:473. PubMed PMC

Tian X, et al. Long non-coding RNA RUNXOR accelerates MDSC-mediated immunosuppression in lung cancer. BMC Cancer. 2018;18(1):660. PubMed PMC

Wang J, et al. The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells. Oncotarget. 2015;6(41):43992–4004. PubMed PMC

Valenti R, et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006;66(18):9290–8. PubMed

Yu X, et al. Neutrophils in cancer: dual roles through intercellular interactions. Oncogene. 2024;43(16):1163–77. PubMed

Zhang X, et al. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol Cancer. 2018;17(1):146. PubMed PMC

Su X, et al. Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis. J Extracell Vesicles. 2023;12(8):e12341. PubMed PMC

Théry C, Amigorena S. The cell biology of antigen presentation in dendritic cells. Curr Opin Immunol. 2001;13(1):45–51. PubMed

Wculek SK, et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24. PubMed

Almand B, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res. 2000;6(5):1755–66. PubMed

Yu S, et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol. 2007;178(11):6867–75. PubMed

Grange C, et al. Role of HLA-G and extracellular vesicles in renal cancer stem cell-induced inhibition of dendritic cell differentiation. BMC Cancer. 2015;15(1):1009. PubMed PMC

Banas R, et al. Amnion-Derived Multipotent Progenitor Cells Inhibit Blood Monocyte Differentiation into Mature Dendritic Cells. Cell Transplant. 2014;23(9):1111–25. PubMed

Hargadon KM. Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity. Front Immunol. 2013;4:192. PubMed PMC

Sombroek CC, et al. Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol. 2002;168(9):4333–43. PubMed

Salimu J, et al. Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J Extracell Vesicles. 2017;6(1):1368823. PubMed PMC

Kim J, et al. Cyclooxygenase-2 expression is induced by celecoxib treatment in lung cancer cells and is transferred to neighbor cells via exosomes. Int J Oncol. 2018;52(2):613–20. PubMed

Mignot G, et al. Tumor exosome-mediated MDSC activation. Am J Pathol. 2011;178(3):1403–4 (author reply 1404-5). PubMed PMC

Vasaturo A, et al. Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go. Front Immunol. 2013;4:417. PubMed PMC

Gao J, et al. Expression profiles and clinical value of plasma exosomal Tim-3 and Galectin-9 in non-small cell lung cancer. Biochem Biophys Res Commun. 2018;498(3):409–15. PubMed

Wang M, et al. Exosomal LGALS9 in the cerebrospinal fluid of glioblastoma patients suppressed dendritic cell antigen presentation and cytotoxic T-cell immunity. Cell Death Dis. 2020;11(10):896. PubMed PMC

Maus RLG, et al. Human Melanoma-Derived Extracellular Vesicles Regulate Dendritic Cell Maturation. Front Immunol. 2017;8:358. PubMed PMC

Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci. 2012;109(17):6662–7. PubMed PMC

Chauhan S, et al. Surface Glycoproteins of Exosomes Shed by Myeloid-Derived Suppressor Cells Contribute to Function. J Proteome Res. 2017;16(1):238–46. PubMed PMC

O’Reilly C, et al. Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities. Med Res Rev. 2016;36(3):440–60. PubMed

Wu H, et al. Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surg Oncol. 2012;106(4):462–8. PubMed

Tamura R, et al. Dual Role of Macrophage in Tumor Immunity. Immunotherapy. 2018;10(10):899–909. PubMed

Kim H, et al. Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing. Adv Sci. 2019;6(20):1900513. PubMed PMC

Li B, et al. Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1+ TAM expansion. Oncogenesis. 2019;8(3):17. PubMed PMC

Nahand JS, et al. Exosomal MicroRNAs: Novel Players in Cervical Cancer. Epigenomics. 2020;12(18):1651–60. PubMed

Pritchard A, et al. Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization. Cells. 2020;9(5):1303. PubMed PMC

Lu Q, et al. Hypoxic Tumor-Derived Exosomal Circ0048117 Facilitates M2 Macrophage Polarization Acting as miR-140 Sponge in Esophageal Squamous Cell Carcinoma. Onco Targets Ther. 2020;13:11883–97. PubMed PMC

Dhanyamraju PK. Drug resistance mechanisms in cancers: Execution of pro-survival strategies. J Biomed Res. 2024;38(2):95–121. PubMed PMC

Lee S, et al. Mesenchymal stem cell-derived exosomes suppress proliferation of T cells by inducing cell cycle arrest through p27kip1/Cdk2 signaling. Immunol Lett. 2020;225:16–22. PubMed

Wang M, et al. Lymph node metastasis-derived gastric cancer cells educate bone marrow-derived mesenchymal stem cells via YAP signaling activation by exosomal Wnt5a. Oncogene. 2021;40(12):2296–308. PubMed PMC

Zhou J, et al. Mesenchymal Stem Cell Derived Exosomes in Cancer Progression, Metastasis and Drug Delivery: A Comprehensive Review. J Cancer. 2018;9(17):3129–37. PubMed PMC

Li C, et al. Effects of Michigan Cancer Foundation-7/A New Adriamycin Cell-Derived Exosomes on MCF-7 Cell Apoptosis and Drug Sensitivity Through Ubiquitin Carboxyl-Terminal Hydrolase L1. J Biomater Tissue Eng. 2020;10:1780–5.

Dong C, et al. Hypoxic non-small-cell lung cancer cell-derived exosomal miR-21 promotes resistance of normoxic cell to cisplatin. Onco Targets Ther. 2019;12:1947–56. PubMed PMC

Yue X, Lan F, Xia T. Hypoxic Glioma Cell-Secreted Exosomal miR-301a Activates Wnt/β-catenin Signaling and Promotes Radiation Resistance by Targeting TCEAL7. Mol Ther. 2019;27(11):1939–49. PubMed PMC

Abe T, Barber GN. Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1. J Virol. 2014;88(10):5328–41. PubMed PMC

Takahashi A, et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun. 2017;8(1):15287. PubMed PMC

Ma Y, et al. Recent advances in critical nodes of embryo engineering technology. Theranostics. 2021;11(15):7391–424. PubMed PMC

Yim KHW, et al. Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks. Cancers. 2020;12(12):3696. PubMed PMC

Sansone P, et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc Natl Acad Sci. 2017;114(43):E9066–75. PubMed PMC

Tripisciano C, et al. Extracellular Vesicles Derived From Platelets, Red Blood Cells, and Monocyte-Like Cells Differ Regarding Their Ability to Induce Factor XII-Dependent Thrombin Generation. Front Cell Dev Biol. 2020;8:298. PubMed PMC

Clayton A, et al. Considerations towards a roadmap for collection, handling and storage of blood extracellular vesicles. J Extracell Vesicles. 2019;8(1):1647027. PubMed PMC

Karimi N, et al. Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins. Cell Mol Life Sci. 2018;75(15):2873–86. PubMed PMC

Erdbrügger U, et al. Urinary extracellular vesicles: A position paper by the Urine Task Force of the International Society for Extracellular Vesicles. J Extracell Vesicles. 2021;10(7):e12093. PubMed PMC

Xiao F, et al. Cerebrospinal fluid biomarkers for brain tumor detection: clinical roles and current progress. Am J Transl Res. 2020;12(4):1379–96. PubMed PMC

Inubushi S, et al. Oncogenic miRNAs Identified in Tear Exosomes From Metastatic Breast Cancer Patients. Anticancer Res. 2020;40(6):3091. PubMed

Liangsupree T, Multia E, Riekkola ML. Modern isolation and separation techniques for extracellular vesicles. J Chromatogr A. 2021;1636:461773. PubMed

Van Deun J, et al. The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J Extracell Vesicles. 2014;3(1). PubMed PMC

Macías M, et al. Comparison of six commercial serum exosome isolation methods suitable for clinical laboratories Effect in cytokine analysis. Clin Chem Lab Med. 2019;57(10):1539–45. PubMed

Coumans FAW, et al. Methodological Guidelines to Study Extracellular Vesicles. Circ Res. 2017;120(10):1632–48. PubMed

Cheruvanky A, et al. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am J Physiol-Renal Physiol. 2007;292(5):F1657–61. PubMed PMC

Guo SC, Tao SC, Dawn H. Microfluidics-based on-a-chip systems for isolating and analysing extracellular vesicles. J Extracell Vesicles. 2018;7(1):1508271. PubMed PMC

Morales-Kastresana A, et al. High-fidelity detection and sorting of nanoscale vesicles in viral disease and cancer. J Extracell Vesicles. 2019;8(1):1597603. PubMed PMC

Allenson K, et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann Oncol. 2017;28(4):741–7. PubMed PMC

Melo SA, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177–82. PubMed PMC

Li J, et al. GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer. J Cell Mol Med. 2017;21(5):838–47. PubMed PMC

Castellanos-Rizaldos E, et al. Exosome-Based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients. Clin Cancer Res. 2018;24(12):2944–50. PubMed

Chen I-H, et al. Phosphoproteins in extracellular vesicles as candidate markers for breast cancer. Proc Natl Acad Sci. 2017;114(12):3175–80. PubMed PMC

Zhang P, Zhou X, Zeng Y. Multiplexed immunophenotyping of circulating exosomes on nano-engineered ExoProfile chip towards early diagnosis of cancer. Chem Sci. 2019;10(21):5495–504. PubMed PMC

Lai H, et al. Protein Panel of Serum-Derived Small Extracellular Vesicles for the Screening and Diagnosis of Epithelial Ovarian Cancer. Cancers (Basel). 2022;14(15):3719. PubMed PMC

Turaga SM, et al. Identification of small extracellular vesicle protein biomarkers for pediatric Ewing Sarcoma. Front Mol Bioscie. 2023:10. PubMed PMC

Matsuzaki K, et al. MiR-21–5p in urinary extracellular vesicles is a novel biomarker of urothelial carcinoma. Oncotarget. 2017;8(15):24668–78. PubMed PMC

Armstrong DA, et al. MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer. Mol Cancer. 2015;14(1):194. PubMed PMC

Keklikoglou I, et al. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Biol. 2019;21(2):190–202. PubMed PMC

Tiedemann K, et al. Exosomal Release of L-Plastin by Breast Cancer Cells Facilitates Metastatic Bone Osteolysis. Transl Oncol. 2019;12(3):462–74. PubMed PMC

Zeng Z, et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9(1):5395. PubMed PMC

Meltzer S, et al. Circulating Exosomal miR-141-3p and miR-375 in Metastatic Progression of Rectal Cancer. Transl Oncol. 2019;12(8):1038–44. PubMed PMC

Fu F, et al. Circulating Exosomal miR-17-5p and miR-92a-3p Predict Pathologic Stage and Grade of Colorectal Cancer. Transl Oncol. 2018;11(2):221–32. PubMed PMC

Franz C, et al. Protective effect of miR-18a in resected liver metastases of colorectal cancer and FOLFOX treatment. Cancer Rep (Hoboken). 2023;6(12):e1899. PubMed PMC

Peng Z-Y, Gu R-H, Yan B. Downregulation of exosome-encapsulated miR-548c-5p is associated with poor prognosis in colorectal cancer. J Cell Biochem. 2019;120(2):1457–63. PubMed

Shao Y, et al. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis. 2018;39(11):1368–79. PubMed

Bijnsdorp IV, et al. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients. J Extracell Vesicles. 2013;2(0):S11. PubMed PMC

Stecklein SR, et al. Extracellular vesicle-derived non-coding RNAs to predict outcome in patients with triple-negative breast cancer (TNBC) with residual disease (RD). J Clin Oncol. 2023;41(16_suppl):578–578.

Morini M, et al. Exosomal microRNAs from longitudinal liquid biopsies for the prediction of response to induction chemotherapy in high-risk neuroblastoma patients: A proof of concept SIOPEN study. Cancers (Basel). 2019;11(10):1476. PubMed PMC

Yuwen D, et al. Prognostic Role of Circulating Exosomal miR-425-3p for the Response of NSCLC to Platinum-Based Chemotherapy. Cancer Epidemiol Biomarkers Prev. 2019;28(1):163–73. PubMed

Atay S, et al. Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers. Mol Cell Proteomics. 2018;17(3):495–515. PubMed PMC

Li M, et al. WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1. J Extracell Vesicles. 2021;10(4):e12067. PubMed PMC

Chen G, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560(7718):382–6. PubMed PMC

Porcelli L, et al. uPAR⁺ extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients. J Immunother Cancer. 2021;9(5):e002372. PubMed PMC

Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol. 2021;16(7):748–59. PubMed

Lener T, et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles. 2015;4:30087. PubMed PMC

Dai J, et al. Exosomes: key players in cancer and potential therapeutic strategy. Signal Transduct Target Ther. 2020;5(1):145. PubMed PMC

Fujita M, et al. The urgent need for clear and concise regulations on exosome-based interventions. Stem Cell Reports. 2024;19(11):1517–9. PubMed PMC

Gimona M, et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy. 2021;23(5):373–80. PubMed

Silva AKA, et al. Development of extracellular vesicle-based medicinal products: A position paper of the group “Extracellular Vesicle translatiOn to clinicaL perspectiVEs - EVOLVE France.” Adv Drug Deliv Rev. 2021;179:114001. PubMed

Beetler DJ, et al. The evolving regulatory landscape in regenerative medicine. Mol Aspects Med. 2023;91:101138. PubMed PMC

Wiklander OPB, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4(1):26316. PubMed PMC

Lai CP, et al. Dynamic Biodistribution of Extracellular Vesicles in Vivo Using a Multimodal Imaging Reporter. ACS Nano. 2014;8(1):483–94. PubMed PMC

Kooijmans SAA, et al. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release. 2016;224:77–85. PubMed

McVey MJ, et al. Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat. Blood. 2021;137(5):690–701. PubMed

Zhu X, et al. Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells. J Extracell Vesicles. 2017;6(1):1324730. PubMed PMC

de Abreu RC, et al. Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat Rev Cardiol. 2020;17(11):685–97. PubMed PMC

Escudier B, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med. 2005;3(1):10. PubMed PMC

Van Delen M, et al. A systematic review and meta-analysis of clinical trials assessing safety and efficacy of human extracellular vesicle-based therapy. J Extracell Vesicles. 2024;13(7):e12458. PubMed PMC

Fusco C, et al. Extracellular vesicles as human therapeutics: A scoping review of the literature. J Extracell Vesicles. 2024;13(5):e12433. PubMed PMC

Jung I, et al. Modification of immune cell-derived exosomes for enhanced cancer immunotherapy: current advances and therapeutic applications. Exp Mol Med. 2024;56(1):19–31. PubMed PMC

Wang C-K, Tsai T-H, Lee C-H. Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes. Clin Transl Sci. 2024;17(8):e13904. PubMed PMC

Weng Z, et al. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J Hematol Oncol. 2021;14(1):136. PubMed PMC

Tan F, et al. Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther. 2024;9(1):17. PubMed PMC

Chen Y-F, et al. Exosomes: a review of biologic function, diagnostic and targeted therapy applications, and clinical trials. J Biomed Sci. 2024;31(1):67. PubMed PMC

Lin H, et al. Therapeutic potential of extracellular vesicles from diverse sources in cancer treatment. Eur J Med Res. 2024;29(1):350. PubMed PMC

Li J, Wang J, Chen Z. Emerging role of exosomes in cancer therapy: progress and challenges. Mol Cancer. 2025;24(1):13. PubMed PMC

Kim SM, et al. Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting. J Control Release. 2017;266:8–16. PubMed

McAndrews KM, et al. Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic Kras(G12D) in pancreatic cancer. Life Sci Alliance. 2021;4(9):e202000875. PubMed PMC

Usman WM, et al. Efficient RNA drug delivery using red blood cell extracellular vesicles. Nat Commun. 2018;9(1):2359. PubMed PMC

Li Z, et al. In Vitro and in Vivo RNA Inhibition by CD9-HuR Functionalized Exosomes Encapsulated with miRNA or CRISPR/dCas9. Nano Lett. 2019;19(1):19–28. PubMed

Liu W, et al. Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics. Precis Clin Med. 2021;4(3):179–91. PubMed PMC

Behr M, et al. In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges. Acta Pharm Sin B. 2021;11(8):2150–71. PubMed PMC

Fan X, et al. A comprehensive review of engineered exosomes from the preparation strategy to therapeutic applications. Biomater Sci. 2024;12(14):3500–21. PubMed

Dooley K, et al. A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties. Mol Ther. 2021;29(5):1729–43. PubMed PMC

Lu Y, et al. CRISPR-Cas9 delivery strategies with engineered extracellular vesicles. Mol Ther Nucleic Acids. 2023;34:102040. PubMed PMC

Xu Q, et al. Tropism-facilitated delivery of CRISPR/Cas9 system with chimeric antigen receptor-extracellular vesicles against B-cell malignancies. J Control Release. 2020;326:455–67. PubMed

Noh S, et al. Exploring Membrane-tethering Technology for Proteins as a Versatile Tool for Uncovering Novel Disease Targets and Advancing Biotherapeutic Development. Isr J Chem. 2023;63(10–11):e202300046.

Besse B, et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. OncoImmunology. 2016;5(4):e1071008. PubMed PMC

Cheng L, Wang Y, Huang L. Exosomes from M1-Polarized Macrophages Potentiate the Cancer Vaccine by Creating a Pro-inflammatory Microenvironment in the Lymph Node. Mol Ther. 2017;25(7):1665–75. PubMed PMC

Enomoto Y, et al. Cytokine-enhanced cytolytic activity of exosomes from NK Cells. Cancer Gene Ther. 2022;29(6):734–49. PubMed PMC

Zhou J, et al. miR-224-5p-enriched exosomes promote tumorigenesis by directly targeting androgen receptor in non-small cell lung cancer. Mol Ther Nucleic Acids. 2021;23:1217–28. PubMed PMC

Kaban K, et al. Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer. Cancers (Basel). 2021;13(10):2397. PubMed PMC

Lv Q, et al. Thermosensitive Exosome-Liposome Hybrid Nanoparticle-Mediated Chemoimmunotherapy for Improved Treatment of Metastatic Peritoneal Cancer. Advanced Science. 2020;7(18):2000515. PubMed PMC

Hiltbrunner S, et al. Exosomal cancer immunotherapy is independent of MHC molecules on exosomes. Oncotarget. 2016;7(25):38707–17. PubMed PMC

Xu Z, et al. Exosome-based immunotherapy: a promising approach for cancer treatment. Mol Cancer. 2020;19(1):160. PubMed PMC

André F, et al. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol. 2004;172(4):2126–36. PubMed

Zitvogel L, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nat Med. 1998;4(5):594–600. PubMed

Näslund TI, et al. Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity. J Immunol. 2013;190(6):2712–9. PubMed

Segura E, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood. 2005;106(1):216–23. PubMed

Villata S, Canta M, Cauda V. EVs and Bioengineering: From Cellular Products to Engineered Nanomachines. Int J Mol Sci. 2020;21(17):6048. PubMed PMC

Kučuk N, et al. Exosomes Engineering and Their Roles as Therapy Delivery Tools, Therapeutic Targets, and Biomarkers. Int J Mol Sci. 2021;22(17):9543. PubMed PMC

Gutierrez-Millan C, et al. Advances in Exosomes-Based Drug Delivery Systems. Macromol Biosci. 2021;21(1):2000269. PubMed

Zhang M, et al. Engineered exosomes from different sources for cancer-targeted therapy. Signal Transduct Target Ther. 2023;8(1):124. PubMed PMC

Li M, et al. Horizontal transfer of exosomal CXCR4 promotes murine hepatocarcinoma cell migration, invasion and lymphangiogenesis. Gene. 2018;676:101–9. PubMed

Zhang F, et al. CXCR4-containing exosomes derived from cancer associated fibroblasts promote epithelial mesenchymal transition in ovarian clear cell carcinoma. Open Med J. 2022;9:e187422032211040.

Xu S, et al. Engineered mesenchymal stem cell-derived exosomes with high CXCR4 levels for targeted siRNA gene therapy against cancer. Nanoscale. 2022;14(11):4098–113. PubMed

Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discovery. 2023;22(2):101–26. PubMed PMC

Wang L, et al. Exosomes containing miRNAs targeting HER2 synthesis and engineered to adhere to HER2 on tumor cells surface exhibit enhanced antitumor activity. J Nanobiotechnol. 2020;18(1):153. PubMed PMC

National Library of Medicine. Phase 1 study of macrophage reprogramming agent, exoASO-STAT6 (CDK-004), in patients with advanced Hepatocellular Carcinoma (HCC) and patients with liver metastases from either primary gastric Cancer or Colorectal Cancer (CRC). Bethesda (MD): National Library of Medicine (US); [updated 2023 Jun 01; cited 2025 Mar 10]. Available from: https://clinicaltrials.gov/study/NCT05375604.

Tian Y, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):2383–90. PubMed

Liu C, Xia C, Xia C. Biology and function of exosomes in tumor immunotherapy. Biomed Pharmacother. 2023;169:115853. PubMed

Xu Z, et al. A near-infrared light-responsive extracellular vesicle as a “Trojan horse” for tumor deep penetration and imaging-guided therapy. Biomaterials. 2021;269:120647. PubMed

Cheng L, et al. Gene-engineered exosomes-thermosensitive liposomes hybrid nanovesicles by the blockade of CD47 signal for combined photothermal therapy and cancer immunotherapy. Biomaterials. 2021;275:120964. PubMed

Du J, et al. Designer exosomes for targeted and efficient ferroptosis induction in cancer via chemo-photodynamic therapy. Theranostics. 2021;11(17):8185–96. PubMed PMC

Dao A, et al. Engineered Exosomes as a Photosensitizer Delivery Platform for Cancer Photodynamic Therapy. ChemMedChem. 2022;17(10):e202200119. PubMed

Ho J, Chaiswing L, St DK. Clair, Extracellular Vesicles and Cancer Therapy: Insights into the Role of Oxidative Stress. Antioxidants. 2022;11(6):1194. PubMed PMC

Jiang H, et al. Drug-induced oxidative stress in cancer treatments: Angel or devil? Redox Biol. 2023;63:102754. PubMed PMC

Jahangiri B, et al. Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches. Biochim Biophys Acta Mol Basis Dis. 2022;1868(10):166484. PubMed

Kim W, et al. Cellular Stress Responses in Radiotherapy. Cells. 2019;8(9):1105. PubMed PMC

Kalluri R, McAndrews KM. The role of extracellular vesicles in cancer. Cell. 2023;186(8):1610–26. PubMed PMC

Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479–96. PubMed PMC

Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011;21(1):103–15. PubMed PMC

Zou Z, et al. Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis. 2017;22(11):1321–35. PubMed

Tangpong J, et al. Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. Neurobiol Dis. 2006;23(1):127–39. PubMed

Ren X, et al. The triangle of death of neurons: Oxidative damage, mitochondrial dysfunction, and loss of choline-containing biomolecules in brains of mice treated with doxorubicin. Advanced insights into mechanisms of chemotherapy induced cognitive impairment (“chemobrain”) involving TNF-α. Free Radic Biol Med. 2019;134:1–8. PubMed PMC

Suematsu N, et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation. 2003;107(10):1418–23. PubMed

Shringarpure R, et al. 4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer’s disease. Cell Mol Life Sci. 2000;57(12):1802–9. PubMed PMC

Yarana C, et al. Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury. Clin Cancer Res. 2018;24(7):1644–53. PubMed PMC

Yáñez-Mó M, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066. PubMed PMC

van der Pol E, et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64(3):676–705. PubMed

Fenech M, et al. Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis. 2011;26(1):125–32. PubMed

Yokoi A, et al. Mechanisms of nuclear content loading to exosomes. Sci Adv. 2019;5(11):eaax8849. PubMed PMC

Holmgren L, et al. Horizontal transfer of DNA by the uptake of apoptotic bodies. Blood. 1999;93(11):3956–63. PubMed

Fischer S, et al. Indication of Horizontal DNA Gene Transfer by Extracellular Vesicles. PLoS ONE. 2016;11(9):e0163665. PubMed PMC

Cai J, et al. Extracellular vesicle-mediated transfer of donor genomic DNA to recipient cells is a novel mechanism for genetic influence between cells. J Mol Cell Biol. 2013;5(4):227–38. PubMed PMC

Cai J, et al. Transferred BCR/ABL DNA from K562 extracellular vesicles causes chronic myeloid leukemia in immunodeficient mice. PLoS ONE. 2014;9(8):e105200. PubMed PMC

Lee TH, et al. Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells. Biochem Biophys Res Commun. 2014;451(2):295–301. PubMed

Lee TH, et al. Barriers to horizontal cell transformation by extracellular vesicles containing oncogenic H-ras. Oncotarget. 2016;7(32):51991–2002. PubMed PMC

Høyer-Hansen M, Jäättelä M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 2007;14(9):1576–82. PubMed

Walter P, Ron D. The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation. Science. 2011;334(6059):1081–6. PubMed

Zhang W, et al. Endoplasmic reticulum stress—a key guardian in cancer. Cell Death Discovery. 2024;10(1):343. PubMed PMC