Small extracellular vesicles (sEVs) secreted by various types of cells serve as crucial mediators of intercellular communication within the complex tumour microenvironment (TME). Tumour-derived small extracellular vesicles (TDEs) are massively produced and released by tumour cells, recapitulating the specificity of their cell of origin. TDEs encapsulate a variety of RNA species, especially messenger RNAs, microRNAs, long non-coding RNAs, and circular RNAs, which release to the TME plays multifaced roles in cancer progression through mediating cell proliferation, invasion, angiogenesis, and immune evasion. sEVs act as natural delivery vehicles of RNAs and can serve as useful targets for cancer therapy. This review article provides an overview of recent studies on TDEs and their RNA cargo, with emphasis on the role of these RNAs in carcinogenesis.

BIOCEV 1st Faculty of Medicine Charles University Praha Czech Republic

Department of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine University Hospital Motol Charles University Prague Czech Republic

Department of Pathological Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

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Lischnig A, Bergqvist M, Ochiya T, Lässer C. Quantitative proteomics identifies proteins enriched in large and small extracellular vesicles. Mol Cell Proteomics. 2022;21:100273.

Zhou B, Xu K, Zheng X, et al. Application of exosomes as liquid biopsy in clinical diagnosis. Sig Transduct Target Ther. 2020;5:1‐14.

Helwa I, Cai J, Drewry MD, et al. A comparative study of serum exosome isolation using differential ultracentrifugation and three commercial reagents. PLoS One. 2017;12:e0170628.

Arraud N, Linares R, Tan S, et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost. 2014;12:614‐627.

Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541‐550.

Wang T, Nasser MI, Shen J, Qu S, He Q, Zhao M. Functions of exosomes in the triangular relationship between the tumor, inflammation, and immunity in the tumor microenvironment. J Immunol Res. 2019;2019:4197829.

Liu J, Wu S, Zheng X, et al. Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions. Sci Rep. 2020;10:14749.

Kim MS, Haney MJ, Zhao Y, et al. Development of exosome‐encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016;12:655‐664.

Qu J‐L, Qu X‐J, Zhao M‐F, et al. Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation. Dig Liver Dis. 2009;41:875‐880.

Wang J, De Veirman K, Faict S, et al. Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression. J Pathol. 2016;239:162‐173.

Feng Q, Zhang C, Lum D, et al. A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis. Nat Commun. 2017;8:14450.

Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes induce fibroblast differentiation into cancer‐associated fibroblasts through TGFβ signaling. Mol Cancer Res. 2018;16:1196‐1204.

Gu W, Shen Y, Zhang L, et al. The multifaceted involvement of exosomes in tumor progression: induction and inhibition. MedComm. 2020;2021(2):297‐314.

Joshi BS, de Beer MA, Giepmans BNG, Zuhorn IS. Endocytosis of extracellular vesicles and release of their cargo from endosomes. ACS Nano. 2020;14:4444‐4455.

Sancho‐Albero M, Navascués N, Mendoza G, et al. Exosome origin determines cell targeting and the transfer of therapeutic nanoparticles towards target cells. J Nanobiotechnology. 2019;17:16.

Mincheva‐Nilsson L, Baranov V. Cancer exosomes and NKG2D receptor–ligand interactions: impairing NKG2D‐mediated cytotoxicity and anti‐tumour immune surveillance. Semin Cancer Biol. 2014;28:24‐30.

Record M, Subra C, Silvente‐Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol. 2011;81:1171‐1182.

Whiteside TL. Exosomes and tumor‐mediated immune suppression. J Clin Invest. 2016;126:1216‐1223.

Chen H, Wang L, Zeng X, et al. Exosomes, a new star for targeted delivery. Front Cell Dev Biol. 2021;9:751079.

van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213‐228.

Adell MAY, Migliano SM, Upadhyayula S, et al. Recruitment dynamics of ESCRT‐III and Vps4 to endosomes and implications for reverse membrane budding. Elife. 2017;6:1652.

Han Q‐F, Li W‐J, Hu K‐S, et al. Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer. Mol Cancer. 2022;21:207.

Fader CM, Colombo MI. Autophagy and multivesicular bodies: two closely related partners. Cell Death Differ. 2009;16:70‐78.

Bieberich E. Sphingolipids and lipid rafts: novel concepts and methods of analysis. Chem Phys Lipids. 2018;216:114‐131.

Wei D, Zhan W, Gao Y, et al. RAB31 marks and controls an ESCRT‐independent exosome pathway. Cell Res. 2021;31:157‐177.

Robinson H, Ruelcke JE, Lewis A, et al. Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer. Clin Transl Med. 2021;11:e381.

Phuyal S, Hessvik NP, Skotland T, Sandvig K, Llorente A. Regulation of exosome release by glycosphingolipids and flotillins. FEBS J. 2014;281:2214‐2227.

Casari I, Howard JA, Robless EE, Falasca M. Exosomal integrins and their influence on pancreatic cancer progression and metastasis. Cancer Lett. 2021;507:124‐134.

Meister M, Tikkanen R. Endocytic trafficking of membrane‐bound cargo: a Flotillin point of view. Membranes. 2014;4:356‐371.

ten Broeke T, van Niel G, Wauben MHM, Wubbolts R, Stoorvogel W. Endosomally stored MHC class II does not contribute to antigen presentation by dendritic cells at inflammatory conditions. Traffic. 2011;12:1025‐1036.

Buschow SI, Nolte‐'t Hoen ENM, Van Niel G, et al. MHC II in dendritic cells is targeted to lysosomes or T cell‐induced exosomes via distinct multivesicular body pathways. Traffic. 2009;10:1528‐1542.

Dorayappan KDP, Wanner R, Wallbillich JJ, et al. Hypoxia‐induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins. Oncogene. 2018;37:3806‐3821.

Zhang H, Freitas D, Kim HS, et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric‐flow field‐flow fractionation. Nat Cell Biol. 2018;20:332‐343.

Elmallah MIY, Ortega‐Deballon P, Hermite L, Pais‐De‐Barros J, Gobbo J, Garrido C. Lipidomic profiling of exosomes from colorectal cancer cells and patients reveals potential biomarkers. Mol Oncol. 2022;16:2710‐2718.

Wang W, Zhu N, Yan T, et al. The crosstalk: exosomes and lipid metabolism. Cell Commun Signal. 2020;18:119.

Lea J, Sharma R, Yang F, Zhu H, Ward ES, Schroit AJ. Detection of phosphatidylserine‐positive exosomes as a diagnostic marker for ovarian malignancies: a proof of concept study. Oncotarget. 2017;8:14395‐14407.

Yang Y, Wang M, Zhang Y‐Y, Zhao S‐Z, Gu S. The endosomal sorting complex required for transport repairs the membrane to delay cell death. Front Oncol. 2022;12:1007446.

Holliday LS, de Faria LP, Rody WJ. Actin and actin‐associated proteins in extracellular vesicles shed by osteoclasts. Int J Mol Sci. 2019;21:158.

Cho HJ, Baek GO, Yoon MG, et al. Overexpressed proteins in HCC cell‐derived exosomes, CCT8, and Cofilin‐1 are potential biomarkers for patients with HCC. Diagn (Basel). 2021;11:1221.

Statello L, Maugeri M, Garre E, et al. Identification of RNA‐binding proteins in exosomes capable of interacting with different types of RNA: RBP‐facilitated transport of RNAs into exosomes. PLoS One. 2018;13:e0195969.

Glisovic T, Bachorik JL, Yong J, Dreyfuss G. RNA‐binding proteins and post‐transcriptional gene regulation. FEBS Lett. 2008;582:1977‐1986.

Ma L, Singh J, Schekman R. Two RNA‐binding proteins mediate the sorting of miR223 from mitochondria into exosomes. Elife. 2023;12:e85878.

Thapa N, Chwae YJ, Yoo KH, et al. Exosomal delivery of TRAIL and miR‐335 for the treatment of hepatocellular carcinoma (review). Int J Mol Med. 2022;51:3.

Kefaloyianni E. Soluble forms of cytokine and growth factor receptors: mechanisms of generation and modes of action in the regulation of local and systemic inflammation. FEBS Lett. 2022;596:589‐606.

Skotland T, Sandvig K, Llorente A. Lipids in exosomes: current knowledge and the way forward. Prog Lipid Res. 2017;66:30‐41.

Pallares‐Rusiñol A, Moura SL, Martí M, Pividori MI. Electrochemical Genosensing of overexpressed GAPDH transcripts in breast cancer exosomes. Anal Chem. 2023;95:2487‐2495.

Lee BR, Lee TJ, Oh S, et al. Ascorbate peroxidase‐mediated in situ labelling of proteins in secreted exosomes. J Extracell Vesicles. 2022;11:e12239.

Tang KD, Wan Y, Zhang X, et al. Proteomic alterations in salivary exosomes derived from human papillomavirus‐driven oropharyngeal cancer. Mol Diagn Ther. 2021;25:505‐515.

Jiang K, Dong C, Yin Z, et al. Exosome‐derived ENO1 regulates integrin α6β4 expression and promotes hepatocellular carcinoma growth and metastasis. Cell Death Dis. 2020;11:972.

Thakur BK, Zhang H, Becker A, et al. Double‐stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24:766‐769.

Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981‐984.

Li S, Li Y, Chen B, et al. exoRBase: a database of circRNA, lncRNA and mRNA in human blood exosomes. Nucleic Acids Res. 2017;46:D106‐D112.

Prieto‐Vila M, Yoshioka Y, Ochiya T. Biological functions driven by mRNAs carried by extracellular vesicles in cancer. Frontiers in Cell and Developmental Biology [Internet]. 2021;9:620498.

Zhu L, Li J, Gong Y, et al. Exosomal tRNA‐derived small RNA as a promising biomarker for cancer diagnosis. Mol Cancer. 2019;18:74.

Narang P, Shah M, Beljanski V. Exosomal RNAs in diagnosis and therapies. Noncoding RNA Res. 2022;7:7‐15.

Cai A, Hu Y, Zhou Z, et al. PIWI‐interacting RNAs (piRNAs): promising applications as emerging biomarkers for digestive system cancer. Front Mol Biosci. 2022;9:848105.

Liu Q‐W, He Y, Xu WW. Molecular functions and therapeutic applications of exosomal noncoding RNAs in cancer. Exp Mol Med. 2022;54:216‐225.

McKenzie AJ, Hoshino D, Hong NH, et al. KRAS‐MEK signaling controls Ago2 sorting into exosomes. Cell Rep. 2016;15:978‐987.

Hagiwara K, Katsuda T, Gailhouste L, Kosaka N, Ochiya T. Commitment of Annexin A2 in recruitment of microRNAs into extracellular vesicles. FEBS Lett. 2015;589:4071‐4078.

Teng Y, Ren Y, Hu X, et al. MVP‐mediated exosomal sorting of miR‐193a promotes colon cancer progression. Nat Commun. 2017;8:14448.

Zigáčková D, Vaňáčová Š. The role of 3′ end uridylation in RNA metabolism and cellular physiology. Philos Trans R Soc B Biol Sci. 2018;373:20180171.

Ashley J, Cordy B, Lucia D, Fradkin LG, Budnik V, Thomson T. Retrovirus‐like Gag protein Arc1 binds RNA and traffics across synaptic boutons. Cell. 2018;172:262‐274.e11.

Zubarev I, Vladimirtsev D, Vorontsova M, et al. Viral membrane fusion proteins and RNA sorting mechanisms for the molecular delivery by exosomes. Cells. 2021;10:3043.

Han C, Liu T, Yin R. Biomarkers for cancer‐associated fibroblasts. Biomark Res. 2020;8:64.

Yoshida GJ. Regulation of heterogeneous cancer‐associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res. 2020;39:112.

Saatci O, Kaymak A, Raza U, et al. Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer. Nat Commun. 2020;11:2416.

Nilsson M, Adamo H, Bergh A, Halin BS. Inhibition of Lysyl oxidase and Lysyl oxidase‐like enzymes has tumour‐promoting and tumour‐suppressing roles in experimental prostate cancer. Sci Rep. 2016;6:19608.

Quintero‐Fabián S, Arreola R, Becerril‐Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Frontiers in Oncology. 2019;9:1370.

Fang Z, Xu J, Zhang B, et al. The promising role of noncoding RNAs in cancer‐associated fibroblasts: an overview of current status and future perspectives. J Hematol Oncol. 2020;13:154.

Chan JSK, Tan MJ, Sng MK, et al. Cancer‐associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress. Cell Death Dis. 2017;8:e2562.

Pang W, Su J, Wang Y, et al. Pancreatic cancer‐secreted miR‐155 implicates in the conversion from normal fibroblasts to cancer‐associated fibroblasts. Cancer Sci. 2015;106:1362‐1369.

Scognamiglio I, Cocca L, Puoti I, et al. Exosomal microRNAs synergistically trigger stromal fibroblasts in breast cancer. Mol Ther Nucleic Acids. 2022;28:17‐31.

Baroni S, Romero‐Cordoba S, Plantamura I, et al. Exosome‐mediated delivery of miR‐9 induces cancer‐associated fibroblast‐like properties in human breast fibroblasts. Cell Death Dis. 2016;7:e2312.

Yang S‐S, Ma S, Dou H, et al. Breast cancer‐derived exosomes regulate cell invasion and metastasis in breast cancer via miR‐146a to activate cancer associated fibroblasts in tumor microenvironment. Exp Cell Res. 2020;391:111983.

Vaira S, Friday E, Scott K, Conrad S, Turturro F. Wnt/β‐catenin signaling pathway and thioredoxin‐interacting protein (TXNIP) mediate the “glucose sensor” mechanism in metastatic breast cancer‐derived cells MDA‐MB‐231. J Cell Physiol. 2012;227:578‐586.

Likonen D, Pinchasi M, Beery E, et al. Exosomal telomerase transcripts reprogram the microRNA transcriptome profile of fibroblasts and partially contribute to CAF formation. Sci Rep. 2022;12:16415.

Hu T, Hu J. Melanoma‐derived exosomes induce reprogramming fibroblasts into cancer‐associated fibroblasts via Gm26809 delivery. Cell Cycle. 2019;18:3085‐3094.

Wang D, Wang X, Song Y, et al. Exosomal miR‐146a‐5p and miR‐155‐5p promote CXCL12/CXCR7‐induced metastasis of colorectal cancer by crosstalk with cancer‐associated fibroblasts. Cell Death Dis. 2022;13:1‐15.

Zhou Z, Xia G, Xiang Z, et al. A C‐X‐C chemokine receptor type 2‐dominated Cross‐talk between tumor cells and macrophages drives gastric cancer metastasis. Clin Cancer Res. 2019;25:3317‐3328.

Liu R‐Y, Zeng Y, Lei Z, et al. JAK/STAT3 signaling is required for TGF‐β‐induced epithelial‐mesenchymal transition in lung cancer cells. Int J Oncol. 2014;44:1643‐1651.

Raudenska M, Balvan J, Hanelova K, Bugajova M, Masarik M. Cancer‐associated fibroblasts: mediators of head and neck tumor microenvironment remodeling. Biochim Biophys Acta Rev Cancer. 2023;1878:188940.

Krüger‐Genge A, Blocki A, Franke R‐P, Jung F. Vascular endothelial cell biology: an update. Int J Mol Sci. 2019;20:4411.

Kałafut J, Czerwonka A, Anameriç A, et al. Shooting at moving and hidden targets—tumour cell plasticity and the notch Signalling pathway in head and neck squamous cell carcinomas. Cancers (Basel). 2021;13:6219.

Melincovici CS, Bo AB, Mihu C, et al. Vascular endothelial growth factor (VEGF) – key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59:455‐467.

Cross M, Claesson‐Welsh L. Cross MJ, Claesson‐Welsh L. FGF and VEGF function in angiogenesis: signaling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci. 2001;22:201‐207.

Fagiani E, Lorentz P, Kopfstein L, Christofori G. Angiopoietin‐1 and ‐2 exert antagonistic functions in tumor angiogenesis, yet both induce Lymphangiogenesis. Cancer Res. 2011;71:5717‐5727.

Zhang W, Zhou X, Yao Q, Liu Y, Zhang H, Dong Z. HIF‐1‐mediated production of exosomes during hypoxia is protective in renal tubular cells. Am J Physiol Renal Physiol. 2017;313:F906‐F913.

King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.

Martinez MC, Andriantsitohaina R, Christian W, Sebastian M. Microparticles in angiogenesis. Circ Res. 2011;109:110‐119.

Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR‐135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor‐inhibiting HIF‐1. Blood. 2014;124:3748‐3757.

Mahon PC, Hirota K, Semenza GL. FIH‐1: a novel protein that interacts with HIF‐1α and VHL to mediate repression of HIF‐1 transcriptional activity. Genes Dev. 2001;15:2675‐2686.

Hsu Y‐L, Hung J‐Y, Chang W‐A, 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;36:4929‐4942.

Yu M, Yu J, Zhang Y, et al. A novel circRNA‐miRNA‐mRNA network revealed exosomal circ‐ATP10A as a biomarker for multiple myeloma angiogenesis. Bioengineered. 2021;13:667‐683.

Li Y, Chen J, Chen Z, et al. CircGLIS3 promotes high‐grade glioma invasion via modulating Ezrin phosphorylation. Front Cell Dev Biol. 2021;9:663207.

Zhang X, Flores LR, Keeling MC, Sliogeryte K, Gavara N. Ezrin phosphorylation at T567 modulates cell migration, mechanical properties, and cytoskeletal organization. Int J Mol Sci. 2020;21:435.

Cheng Y, Dai X, Yang T, Zhang N, Liu Z, Jiang Y. Low Long noncoding RNA growth arrest‐specific transcript 5 expression in the exosomes of lung cancer cells promotes tumor angiogenesis. J Oncol. 2019;2019:2476175.

Lang H‐L, Hu G‐W, Chen Y, et al. Glioma cells promote angiogenesis through the release of exosomes containing long non‐coding RNA POU3F3. Eur Rev Med Pharmacol Sci. 2017;21:959‐972.

Wang J, Wang C, Li Y, et al. Potential of peptide‐engineered exosomes with overexpressed miR‐92b‐3p in anti‐angiogenic therapy of ovarian cancer. Clin Transl Med. 2021;11:e425.

Moreno CS. SOX4: the unappreciated oncogene. Semin Cancer Biol. 2020;67:57‐64.

Pan S, Zhao X, Shao C, et al. STIM1 promotes angiogenesis by reducing exosomal miR‐145 in breast cancer MDA‐MB‐231 cells. Cell Death Dis. 2021;12:38.

Rodrigues Alves APN, Fernandes JC, Fenerich BA, et al. IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells. Cancer Lett. 2019;456:59‐68.

Cassetta L, Pollard JW. A timeline of tumour‐associated macrophage biology. Nat Rev Cancer. 2023;23:238‐257.

Gao J, Liang Y, Wang L. Shaping polarization of tumor‐associated macrophages in cancer immunotherapy. Front Immunol. 2022;13:888713.

Ying X, Wu Q, Wu X, et al. Epithelial ovarian cancer‐secreted exosomal miR‐222‐3p induces polarization of tumor‐associated macrophages. Oncotarget. 2016;7:43076‐43087.

Zhao S, Mi Y, Guan B, et al. Tumor‐derived exosomal miR‐934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13:156.

Sobierajska K, Wieczorek K, Ciszewski WM, et al. β‐III tubulin modulates the behavior of snail overexpressed during the epithelial‐to‐mesenchymal transition in colon cancer cells. Biochim Biophys Acta. 2016;1863:2221‐2233.

Liang Z, Liu H, Wang F, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes‐mediated macrophage M2 polarization. Cell Death Dis. 2019;10:1‐17.

Li X, Lei Y, Wu M, Li N. Regulation of macrophage activation and polarization by HCC‐derived exosomal lncRNA TUC339. Int J Mol Sci. 2018;19:2958.

Chen T, Liu Y, Li C, et al. Tumor‐derived exosomal circFARSA mediates M2 macrophage polarization via the PTEN/PI3K/AKT pathway to promote non‐small cell lung cancer metastasis. Cancer Treat Res Commun. 2021;28:100412.

Wang X, Luo G, Zhang K, et al. Hypoxic tumor‐derived Exosomal miR‐301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis. Cancer Res. 2018;78:4586‐4598.

Lu Q, Wang X, Zhu J, Fei X, Chen H, Li C. Hypoxic tumor‐derived exosomal Circ0048117 facilitates M2 macrophage polarization acting as miR‐140 sponge in esophageal squamous cell carcinoma. Onco Targets Ther. 2020;13:11883‐11897.

Kumar BV, Connors T, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48:202‐213.

Seder RA, Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol. 2003;4:835‐842.

Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2:735‐747.

Charles A, Janeway J, Travers P, Walport M, Shlomchik MJ. T cell‐mediated cytotoxicity. Immunobiology: The Immune System in Health and Disease. 5th ed. Garland Science; 2001.

Jaime‐Sanchez P, Uranga‐Murillo I, Aguilo N, et al. Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase‐3–dependent spread immunity against endogenous tumor antigens. J Immunother Cancer. 2020;8:e000528.

Huber V, Fais S, Iero M, et al. Human colorectal cancer cells induce T‐cell death through release of Proapoptotic microvesicles: role in immune escape. Gastroenterology. 2005;128:1796‐1804.

Liu J, Fan L, Yu H, et al. Endoplasmic reticulum stress promotes liver cancer cells to release Exosomal miR‐23a‐3p and up‐regulate PD‐L1 expression in macrophages. Hepatology. 2019;70:241‐258.

Chen S‐W, Zhu S‐Q, Pei X, et al. Cancer cell‐derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti‐PD1 resistance by regulating the miR‐934/SHP2 axis in NSCLC. Mol Cancer. 2021;20:144.

Hu Z, Chen G, Zhao Y, et al. Exosome‐derived circCCAR1 promotes CD8 + T‐cell dysfunction and anti‐PD1 resistance in hepatocellular carcinoma. Mol Cancer. 2023;22:55.

Xie W, Liu N, Wang X, Wei L, Xie W, Sheng X. Wilms' tumor 1‐associated protein contributes to chemo‐resistance to cisplatin through the Wnt/β‐catenin pathway in endometrial cancer. Front Oncol. 2021;11:598344.

Li P, Liu C, Yu Z, Wu M. New insights into regulatory T cells: exosome‐ and non‐coding RNA‐mediated regulation of homeostasis and resident Treg cells. Front Immunol. 2016;7:574.

Huang M, Huang X, Huang N. Exosomal circGSE1 promotes immune escape of hepatocellular carcinoma by inducing the expansion of regulatory T cells. Cancer Sci. 2022;113:1968‐1983.

Takimoto T, Wakabayashi Y, Sekiya T, et al. Smad2 and Smad3 are redundantly essential for the TGF‐β–mediated regulation of regulatory T plasticity and Th1 development. J Immunol. 2010;185:842‐855.

Ni C, Fang Q‐Q, Chen W‐Z, et al. Breast cancer‐derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells. Sig Transduct Target Ther. 2020;5:1‐14.

Paskeh MDA, Entezari M, Mirzaei S, et al. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol. 2022;15:83.

Dai J, Su Y, Zhong S, et al. Exosomes: key players in cancer and potential therapeutic strategy. Sig Transduct Target Ther. 2020;5:1‐10.

Lang H‐L, Hu G‐W, Zhang B, et al. Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non‐coding RNA CCAT2. Oncol Rep. 2017;38:785‐798.

Yan W, Wu X, Zhou W, et al. Cancer‐cell‐secreted exosomal miR‐105 promotes tumour growth through the MYC‐dependent metabolic reprogramming of stromal cells. Nat Cell Biol. 2018;20:597‐609.

Lei Y, Huang Y, Lin J, et al. Mxi1 participates in the progression of lung cancer via the microRNA‐300/KLF9/GADD34 axis. Cell Death Dis. 2022;13:1‐12.

Sun L‐H, Tian D, Yang Z‐C, Li J‐L. Exosomal miR‐21 promotes proliferation, invasion and therapy resistance of colon adenocarcinoma cells through its target PDCD4. Sci Rep. 2020;10:8271.

Wang Q, Yang H‐S. The role of Pdcd4 in tumor suppression and protein translation. Biol Cell. 2018;110:169‐177. doi:10.1111/boc.201800014

Gao L, Tang X, He Q, Sun G, Wang C, Qu H. Exosome‐transmitted circCOG2 promotes colorectal cancer progression via miR‐1305/TGF‐β2/SMAD3 pathway. Cell Death Discov. 2021;7:1‐13.

Soleimani A, Pashirzad M, Avan A, Ferns GA, Khazaei M, Hassanian SM. Role of the transforming growth factor‐β signaling pathway in the pathogenesis of colorectal cancer. J Cell Biochem. 2019;120:8899‐8907.

Mao L, Li X, Gong S, et al. Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis. Cancer Gene Ther. 2018;25:248‐259.

Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL‐2 family proteins. Nat Rev Mol Cell Biol. 2019;20:175‐193.

Gong Y, Fan Z, Luo G, et al. The role of necroptosis in cancer biology and therapy. Mol Cancer. 2019;18:100.

Xia X, Wang X, Cheng Z, et al. The role of pyroptosis in cancer: pro‐cancer or pro‐“host”? Cell Death Dis. 2019;10:1‐13.

Chen Z, Wang W, Abdul Razak SR, Han T, Ahmad NH, Li X. Ferroptosis as a potential target for cancer therapy. Cell Death Dis. 2023;14:1‐15.

Hill C, Dellar ER, Baena‐Lopez LA. Caspases help to spread the message via extracellular vesicles. FEBS J. 2023;290:1954‐1972.

Kakarla R, Hur J, Kim YJ, Kim J, Chwae Y‐J. Apoptotic cell‐derived exosomes: messages from dying cells. Exp Mol Med. 2020;52:1‐6.

Hardy M‐P, Audemard É, Migneault F, et al. Apoptotic endothelial cells release small extracellular vesicles loaded with immunostimulatory viral‐like RNAs. Sci Rep. 2019;9:7203.

Crescitelli R, Lässer C, Szabó TG, et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013;2:20677. doi:10.3402/jev.v2i0.20677

Brodeur A, Migneault F, Lanoie M, et al. Apoptotic exosome‐like vesicles transfer specific and functional mRNAs to endothelial cells by phosphatidylserine‐dependent macropinocytosis. Cell Death Dis. 2023;14:449.

Wen Z, Mai Z, Zhu X, et al. Mesenchymal stem cell‐derived exosomes ameliorate cardiomyocyte apoptosis in hypoxic conditions through microRNA144 by targeting the PTEN/AKT pathway. Stem Cell Res Ther. 2020;11:36.

Piao H, Guo S, Wang Y, Zhang J. Exosomal Long non‐coding RNA CEBPA‐AS1 inhibits tumor apoptosis and functions as a non‐invasive biomarker for diagnosis of gastric cancer. Onco Targets Ther. 2020;13:1365‐1374.

Liu Z, Yang Z, He L. Effect of miR‐29a‐3p in exosomes on glioma cells by regulating the PI3K/AKT/HIF‐1α pathway. Mol Med Rep. 2023;27:72.

Zhang H, Deng T, Liu R, et al. CAF secreted miR‐522 suppresses ferroptosis and promotes acquired chemo‐resistance in gastric cancer. Mol Cancer. 2020;19:43.

Su L‐J, Zhang J‐H, Gomez H, et al. Reactive oxygen species‐induced lipid peroxidation in apoptosis, autophagy, and Ferroptosis. Oxid Med Cell Longev. 2019;2019:5080843.

Tian R, Zuo X, Jaoude J, Mao F, Colby J, Shureiqi I. ALOX15 as a suppressor of inflammation and cancer: lost in the link. Prostaglandins Other Lipid Mediat. 2017;132:77‐83.

Zhang H, Wang M, He Y, et al. Chemotoxicity‐induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells. Cell Death Dis. 2021;12:1‐14.

Costa ML, de Andrade RI, Andrade L, Mermelstein C, Coutinho C. Distinct interactions between epithelial and mesenchymal cells control cell morphology and collective migration during sponge epithelial to mesenchymal transition. J Morphol. 2020;281:183‐195.

Haynes J, Srivastava J, Madson N, Wittmann T, Barber DL. Dynamic Actin remodeling during epithelial–mesenchymal transition depends on increased moesin expression. Mol Biol Cell. 2011;22:4750‐4764.

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178‐196.

Li Y, He J, Wang F, et al. Role of MMP‐9 in epithelial‐mesenchymal transition of thyroid cancer. World J Surg Oncol. 2020;18:181.

Li S, Luo W. Matrix metalloproteinase 2 contributes to aggressive phenotype, epithelial‐mesenchymal transition and poor outcome in nasopharyngeal carcinoma. Onco Targets Ther. 2019;12:5701‐5711.

Yeh H‐W, Hsu E‐C, Lee S‐S, et al. PSPC1 mediates TGF‐β1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis. Nat Cell Biol. 2018;20:479‐491.

Coelho BP, Fernandes CFDL, Boccacino JM, et al. Multifaceted WNT signaling at the crossroads between epithelial‐mesenchymal transition and autophagy in glioblastoma. Front Oncol. 2020;10:597743. doi:10.3389/fonc.2020.597743

Wang F, Ma L, Zhang Z, et al. Hedgehog signaling regulates epithelial‐mesenchymal transition in pancreatic cancer stem‐like cells. J Cancer. 2016;7:408‐417.

Akrida I, Bravou V, Papadaki H. The deadly cross‐talk between hippo pathway and epithelial–mesenchymal transition (EMT) in cancer. Mol Biol Rep. 2022;49:10065‐10076.

Begemann D, Anastos H, Kyprianou N. Cell death under epithelial–mesenchymal transition control in prostate cancer therapeutic response. Int J Urol. 2018;25:318‐326.

Cao Z, Livas T, Kyprianou N. Anoikis and EMT: lethal “liaisons” during cancer progression. Crit Rev Oncog. 2016;21:155‐168.

Syn N, Wang L, Sethi G, Thiery J‐P, Goh B‐C. Exosome‐mediated metastasis: from epithelial–mesenchymal transition to escape from Immunosurveillance. Trends Pharmacol Sci. 2016;37:606‐617.

Zhang X, Sai B, Wang F, et al. Hypoxic BMSC‐derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3‐induced EMT. Mol Cancer. 2019;18:40.

Wang L, Yang G, Zhao D, et al. CD103‐positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR‐19b‐3p. Mol Cancer. 2019;18:86.

Lu C, Shan Z, Hong J, Yang L. MicroRNA‐92a promotes epithelial‐mesenchymal transition through activation of PTEN/PI3K/AKT signaling pathway in non‐small cell lung cancer metastasis. Int J Oncol. 2017;51:235‐244.

Shu G, Lu X, Pan Y, et al. Exosomal circSPIRE1 mediates glycosylation of E‐cadherin to suppress metastasis of renal cell carcinoma. Oncogene. 2023;42:1802‐1820.

Chugh S, Meza J, Sheinin YM, Ponnusamy MP, Batra SK. Loss of N‐acetylgalactosaminyltransferase 3 in poorly differentiated pancreatic cancer: augmented aggressiveness and aberrant ErbB family glycosylation. Br J Cancer. 2016;114:1376‐1386.

Chen X, Chen R‐X, Wei W‐S, et al. PRMT5 circular RNA promotes metastasis of urothelial carcinoma of the bladder through sponging miR‐30c to induce epithelial–mesenchymal transition. Clin Cancer Res. 2018;24:6319‐6330.

Huang C‐S, Ho J‐Y, Chiang J‐H, Yu C‐P, Yu D‐S. Exosome‐derived LINC00960 and LINC02470 promote the epithelial‐mesenchymal transition and aggressiveness of bladder cancer cells. Cells. 2020;9:1419.

Peinado H, Zhang H, Matei IR, et al. Pre‐metastatic niches: organ‐specific homes for metastases. Nat Rev Cancer. 2017;17:302‐317.

Zeng Z, Li Y, Pan Y, et al. Cancer‐derived exosomal miR‐25‐3p promotes pre‐metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9:5395.

Kong J, Tian H, Zhang F, et al. Extracellular vesicles of carcinoma‐associated fibroblasts creates a pre‐metastatic niche in the lung through activating fibroblasts. Mol Cancer. 2019;18:175.

Zeng H, Hou Y, Zhou X, et al. Cancer‐associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5‐mediated angiogenesis and vascular permeability in breast cancer. Theranostics. 2022;12:7351‐7370.

Li G, Yi X, Du S, et al. Tumour‐derived exosomal piR‐25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition. Oncogene. 2023;42:421‐433.

Bertrand‐Chapel A, Caligaris C, Fenouil T, et al. SMAD2/3 mediate oncogenic effects of TGF‐β in the absence of SMAD4. Commun Biol. 2022;5:1‐13.

Ye Y, Li S‐L, Ma Y‐Y, et al. Exosomal miR‐141‐3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer. Oncotarget. 2017;8:94834‐94849.

Suzuki A, Guicheux J, Palmer G, et al. Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation. Bone. 2002;30:91‐98.

Rey A, Manen D, Rizzoli R, Ferrari SL, Caverzasio J. Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells. Bone. 2007;41:59‐67.

Ni Q, Zhang H, Shi X, Li X. Exosomal lncRNA HCG18 contributes to cholangiocarcinoma growth and metastasis through mediating miR‐424‐5p/SOX9 axis through PI3K/AKT pathway. Cancer Gene Ther. 2023;30:582‐595.

Panda M, Tripathi SK, Biswal BK. SOX9: an emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta. 2021;1875:188517.

Wang L, Zhang Z, Yu X, et al. SOX9/miR‐203a axis drives PI3K/AKT signaling to promote esophageal cancer progression. Cancer Lett. 2020;468:14‐26.

Jana S, Krishna BM, Singhal J, et al. SOX9: the master regulator of cell fate in breast cancer. Biochem Pharmacol. 2020;174:113789.

Yokoi A, Yoshioka Y, Yamamoto Y, et al. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat Commun. 2017;8:14470.

Hoshino A, Costa‐Silva B, Shen T‐L, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329‐335.

Zahan T, Das PK, Akter SF, et al. Therapy resistance in cancers: phenotypic, metabolic, epigenetic and tumour microenvironmental perspectives. Anticancer Agents Med Chem. 2020;20:2190‐2206.

Bebawy M, Combes V, Lee E, et al. Membrane microparticles mediate transfer of P‐glycoprotein to drug sensitive cancer cells. Leukemia. 2009;23:1643‐1649.

Zhong Y, Li H, Li P, et al. Exosomes: a new pathway for cancer drug resistance. Front Oncol. 2021;11:743556.

Li S, Yi M, Dong B, Jiao Y, Luo S, Wu K. The roles of exosomes in cancer drug resistance and its therapeutic application. Clin Transl Med. 2020;10:e257.

Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019;18:75.

Zhang P‐F, Gao C, Huang X‐Y, et al. Cancer cell‐derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti‐PD1 therapy in hepatocellular carcinoma. Mol Cancer. 2020;19:110.

Hu X, Wen Y, Tan L, et al. Exosomal Long non‐coding RNA ANCR mediates drug resistance in osteosarcoma. Front Oncol. 2022;11:735254.

Shi Y, Zou Y, Guo Y, Liu Y, Wang Q. Exosomal transfer of miR‐548aq‐3p confers cisplatin resistance via MED12 downregulation in epithelial ovarian cancer. Am J Cancer Res. 2023;13:1999‐2012.

Huang S, Hölzel M, Knijnenburg T, et al. MED12 controls the response to multiple cancer drugs through regulation of TGF‐β receptor signaling. Cell. 2012;151:937‐950.

Zhang S, O'Regan R, Xu W. The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics. Cancer. 2020;126:939‐948.

Au Yeung CL, Co N‐N, Tsuruga T, et al. Exosomal transfer of stroma‐derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150.

Shakeri R, Kheirollahi A, Davoodi J. Contribution of Apaf‐1 to the pathogenesis of cancer and neurodegenerative diseases. Biochimie. 2021;190:91‐110.

Yu T, Wang X, Zhi T, et al. Delivery of MGMT mRNA to glioma cells by reactive astrocyte‐derived exosomes confers a temozolomide resistance phenotype. Cancer Lett. 2018;433:210‐220.