The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy

Abstract

Exosomes are indispensable for intercellular communications. Tumor microenvironment (TME) is the living environment of tumor cells, which is composed of various components, including immune cells. Based on TME, immunotherapy has been recently developed for eradicating cancer cells by reactivating antitumor effect of immune cells. The communications between tumor cells and TME are crucial for tumor development, metastasis, and drug resistance. Exosomes play an important role in mediating these communications and regulating the reprogramming of TME, which affects the sensitivity of immunotherapy. Therefore, it is imperative to investigate the role of exosomes in TME reprogramming and the impact of exosomes on immunotherapy. Here, we review the communication role of exosomes in regulating TME remodeling and the efficacy of immunotherapy, as well as summarize the underlying mechanisms. Furthermore, we also introduce the potential application of the artificially modified exosomes as the delivery systems of antitumor drugs. Further efforts in this field will provide new insights on the roles of exosomes in intercellular communications of TME and cancer progression, thus helping us to uncover effective strategies for cancer treatment.

Keywords

exosomes / immunotherapy / intercellular communications / tumor microenvironment / tumor therapy

References

1	E Yang, X Wang, Z Gong, M Yu, H Wu, D Zhang. Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression. Signal Transduct Target Ther. 2020;5(1):242.
2	NM Anderson, MC Simon. The tumor microenvironment. Curr Biol. 2020;30(16):R921-R925.
3	DC Hinshaw, LA Shevde. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79(18):4557-4566.
4	X Lei, Y Lei, JK Li, et al. Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy. Cancer Lett. 2020;470:126-133.
5	LB Kennedy, AKS Salama. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70(2):86-104.
6	B Rowshanravan, N Halliday, DM Sansom. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67.
7	C Qi, J Gong, J Li, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28(6):1189-1198.
8	M Saxena, SH van der Burg, CJM Melief, N Bhardwaj. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21(6):360-378.
9	R Kalluri, VS LeBleu. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.
10	LM Doyle, MZ Wang. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8(7):727.
11	DM Pegtel, SJ Gould. Exosomes. Annu Rev Biochem. 2019;88:487-514.
12	WJ Gu, YW Shen, LJ Zhang, et al. The multifaceted involvement of exosomes in tumor progression: induction and inhibition. MedComm. 2021;2(3):297-314.
13	Q He, A Ye, W Ye, et al. Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1. Cell Death Dis. 2021;12(6):576.
14	Y Liang, L Duan, J Lu, J Xia. Engineering exosomes for targeted drug delivery. Theranostics. 2021;11(7):3183-3195.
15	X Zhang, H Zhang, J Gu, et al. Engineered extracellular vesicles for cancer therapy. Adv Mater. 2021;33(14):e2005709.
16	YY Janjigian, K Shitara, M Moehler, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40.
17	AB Benson, MI D'Angelica, DE Abbott, et al. Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(5):541-565.
18	AB Benson, AP Venook, MM Al-Hawary, et al. Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(10):1139-1167.
19	M Reina-Campos, NE Scharping, AW Goldrath. CD8(+) T cell metabolism in infection and cancer. Nat Rev Immunol. 2021;21(11):718-738.
20	K Kersten, KH Hu, AJ Combes, et al. Spatiotemporal co-dependency between macrophages and exhausted CD8(+) T cells in cancer. Cancer Cell. 2022;40(6):624-638. e9.
21	M St Paul, PS Ohashi. The roles of CD8(+) T cell subsets in antitumor immunity. Trends Cell Biol. 2020;30(9):695-704.
22	Z Hu, G Chen, Y Zhao, et al. Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma. Mol Cancer. 2023;22(1):55.
23	C Yang, S Wu, Z Mou, et al. Exosome-derived circTRPS1 promotes malignant phenotype and CD8+ T cell exhaustion in bladder cancer microenvironments. Mol Ther. 2022;30(3):1054-1070.
24	G Li, W Chen, K Jiang, et al. Exosome-mediated delivery of miR-519e-5p promotes malignant tumor phenotype and CD8+ T-cell exhaustion in metastatic PTC. J Clin Endocrinol Metab. 2023:dgad725.
25	X Wang, H Shen, G Zhangyuan, 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.
26	J Liu, S Wu, X Zheng, et al. Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions. Sci Rep. 2020;10(1):14749.
27	S-W Chen, S-Q Zhu, X Pei, 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(1):144.
28	Y Yuan, L Wang, D Ge, et al. Exosomal O-GlcNAc transferase from esophageal carcinoma stem cell promotes cancer immunosuppression through up-regulation of PD-1 in CD8(+) T cells. Cancer Lett. 2021;500:98-106.
29	L Guan, B Wu, T Li, et al. HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors. Nat Commun. 2022;13(1):4078.
30	S Shin, H Ko, CH Kim, et al. Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy. Nat Mater. 2023;22(5):656-665.
31	J Saravia, NM Chapman, H Chi. Helper T cell differentiation. Cell Mol Immunol. 2019;16(7):634-643.
32	A Basu, G Ramamoorthi, G Albert, et al. Differentiation and regulation of T(H) cells: a balancing act for cancer immunotherapy. Front Immunol. 2021;12:669474.
33	Z Asadzadeh, H Mohammadi, E Safarzadeh, et al. The paradox of Th17 cell functions in tumor immunity. Cell Immunol. 2017;322:15-25.
34	L Guery, S Hugues. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int. 2015;2015:314620.
35	M Tosolini, A Kirilovsky, B Mlecnik, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71(4):1263-1271.
36	F Liu, Z Bu, F Zhao, D Xiao. Increased T-helper 17 cell differentiation mediated by exosome-mediated microRNA-451 redistribution in gastric cancer infiltrated T cells. Cancer Sci. 2018;109(1):65-73.
37	J Sun, H Jia, X Bao, et al. Tumor exosome promotes Th17 cell differentiation by transmitting the lncRNA CRNDE-h in colorectal cancer. Cell Death Dis. 2021;12(1):123.
38	S Li, R Na, X Li, Y Zhang, T Zheng. Targeting interleukin-17 enhances tumor response to immune checkpoint inhibitors in colorectal cancer. Biochim Biophys Acta Rev Cancer. 2022;1877(4):188758.
39	A Tanaka, S Sakaguchi. Targeting Treg cells in cancer immunotherapy. Eur J Immunol. 2019;49(8):1140-1146.
40	M Szajnik, M Czystowska, MJ Szczepanski, M Mandapathil, TL Whiteside. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS One. 2010;5(7):e11469.
41	M Wang, Z Qin, J Wan, et al. Tumor-derived exosomes drive pre-metastatic niche formation in lung via modulating CCL1+ fibroblast and CCR8+ Treg cell interactions. Cancer Immunol Immunother. 2022;71(11):2717-2730.
42	T Ning, J Li, Y He, et al. Exosomal miR-208b related with oxaliplatin resistance promotes Treg expansion in colorectal cancer. Mol Ther. 2021;29(9):2723-2736.
43	C Ni, Q-Q Fang, W-Z Chen, et al. Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells. Signal Transduct Target Ther. 2020;5(1):41.
44	J Li, L Sun, Y Chen, et al. Gastric cancer-derived exosomal miR-135b-5p impairs the function of Vgamma9Vdelta2 T cells by targeting specificity protein 1. Cancer Immunol Immunother. 2022;71(2):311-325.
45	T Zhu, Z Chen, G Jiang, X Huang. Sequential targeting hybrid nanovesicles composed of chimeric antigen receptor T-cell-derived exosomes and liposomes for enhanced cancer immunochemotherapy. ACS Nano. 2023;17(17):16770-16786.
46	JG Cyster, CDC Allen. B cell responses: cell interaction dynamics and decisions. Cell. 2019;177(3):524-540.
47	GS Kinker, GAF Vitiello, WAS Ferreira, AS Chaves, VC Cordeiro de Lima, TDS Medina. B cell orchestration of anti-tumor immune responses: a matter of cell localization and communication. Front Cell Dev Biol. 2021;9:678127.
48	S Biswas, G Mandal, KK Payne, et al. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature. 2021;591(7850):464-470.
49	BA Helmink, SM Reddy, J Gao, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549-555.
50	F Petitprez, A de Reynies, EZ Keung, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577(7791):556-560.
51	JC Schroeder, L Puntigam, L Hofmann, et al. Circulating exosomes inhibit B cell proliferation and activity. Cancers (Basel). 2020;12(8):2110.
52	Z Xie, J Xia, M Jiao, et al. Exosomal lncRNA HOTAIR induces PDL1(+) B cells to impede anti-tumor immunity in colorectal cancer. Biochem Biophys Res Commun. 2023;644:112-121.
53	S Li, B Mirlekar, BM Johnson, et al. STING-induced regulatory B cells compromise NK function in cancer immunity. Nature. 2022;610(7931):373-380.
54	RJ Harris, Z Willsmore, R Laddach, et al. Enriched circulating and tumor-resident TGF-beta(+) regulatory B cells in patients with melanoma promote FOXP3(+) Tregs. Oncoimmunology. 2022;11(1):2104426.
55	L Ye, Q Zhang, Y Cheng, et al. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1(+) regulatory B cell expansion. J Immunother Cancer. 2018;6(1):145.
56	AM Abel, C Yang, MS Thakar, S Malarkannan. Natural killer cells: development, maturation, and clinical utilization. Front Immunol. 2018;9:1869.
57	JA Myers, JS Miller. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2021;18(2):85-100.
58	CH Wu, J Li, L Li, et al. Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells. J Extracell Vesicles. 2019;8(1):1588538.
59	L Moretta, G Pietra, E Montaldo, et al. Human NK cells: from surface receptors to the therapy of leukemias and solid tumors. Front Immunol. 2014;5:87.
60	AL Di Pace, N Tumino, F Besi, et al. Characterization of human NK cell-derived exosomes: role of DNAM1 receptor in exosome-mediated cytotoxicity against tumor. Cancers (Basel). 2020;12(3):661.
61	HY Kim, HK Min, HW Song, et al. Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models. Drug Deliv. 2022;29(1):2897-2911.
62	MC Svensson, CF Warfvinge, R Fristedt, et al. The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma. Oncotarget. 2017;8(42):72108-72126.
63	C Zhang, J Roder, A Scherer, et al. Bispecific antibody-mediated redirection of NKG2D-CAR natural killer cells facilitates dual targeting and enhances antitumor activity. J Immunother Cancer. 2021;9(10):e002980.
64	R Parihar, C Rivas, M Huynh, et al. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunol Res. 2019;7(3):363-375.
65	NK Wolf, DU Kissiov, DH Raulet. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol. 2023;23(2):90-105.
66	F Cichocki, R Bjordahl, S Gaidarova, et al. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. Sci Transl Med. 2020;12(568):eaaz5618.
67	N Albinger, R Pfeifer, M Nitsche, et al. Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia. Blood Cancer J. 2022;12(4):61.
68	H Dong, JD Ham, G Hu, et al. Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia. Proc Natl Acad Sci USA. 2022;119(25):e2122379119.
69	E Liu, D Marin, P Banerjee, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545-553.
70	Y Huang, Y Luo, W Ou, et al. Correction to: exosomal lncRNA SNHG10 derived from colorectal cancer cells suppresses natural killer cell cytotoxicity by upregulating INHBC. Cancer Cell Int. 2022;22(1):55.
71	PF Zhang, C Gao, XY Huang, 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(1):110.
72	T Nakano, IH Chen, CC Wang, et al. Circulating exosomal miR-92b: its role for cancer immunoediting and clinical value for prediction of posttransplant hepatocellular carcinoma recurrence. Am J Transplant. 2019;19(12):3250-3262.
73	H Luo, Y Zhou, J Zhang, et al. NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions. Front Immunol. 2023;13:1087689.
74	B Tao, R Du, X Zhang, et al. Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy. J Controlled Release. 2023;363:692-706.
75	AE Marciscano, N Anandasabapathy. The role of dendritic cells in cancer and anti-tumor immunity. Semin Immunol. 2021;52:101481.
76	S Balan, M Saxena, N Bhardwaj. Dendritic cell subsets and locations. Int Rev Cell Mol Biol. 2019;348:1-68.
77	S Spranger, D Dai, B Horton, TF Gajewski. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell. 2017;31(5):711-723. e4.
78	Z Lu, B Zuo, R Jing, et al. Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. J Hepatol. 2017;67(4):739-748.
79	J Lu, N Wei, S Zhu, et al. Exosomes derived from dendritic cells infected with Toxoplasma gondii show antitumoral activity in a mouse model of colorectal cancer. Front Oncol. 2022;12:899737.
80	M Hinata, A Kunita, H Abe, et al. Exosomes of Epstein-Barr virus-associated gastric carcinoma suppress dendritic cell maturation. Microorganisms. 2020;8(11):1776.
81	O Markov, A Oshchepkova, N Mironova. Immunotherapy based on dendritic cell-targeted/-derived extracellular vesicles—a novel strategy for enhancement of the anti-tumor immune response. Front Pharmacol. 2019;10:1152.
82	S Hao, O Bai, F Li, J Yuan, S Laferte, J Xiang. Mature dendritic cells pulsed with exosomes stimulate efficient cytotoxic T-lymphocyte responses and antitumour immunity. Immunology. 2007;120(1):90-102.
83	X Zhong, Y Zhou, Y Cao, et al. Enhanced antitumor efficacy through microwave ablation combined with a dendritic cell-derived exosome vaccine in hepatocellular carcinoma. Int J Hyperthermia. 2020;37(1):1210-1218.
84	CR Perez, M De Palma. Engineering dendritic cell vaccines to improve cancer immunotherapy. Nat Commun. 2019;10(1):5408.
85	M Sadeghzadeh, S Bornehdeli, H Mohahammadrezakhani, et al. Dendritic cell therapy in cancer treatment; the state-of-the-art. Life Sci. 2020;254:117580.
86	Z Du, Z Huang, X Chen, et al. Modified dendritic cell-derived exosomes activate both NK cells and T cells through the NKG2D/NKG2D-L pathway to kill CML cells with or without T315I mutation. Exp Hematol Oncol. 2022;11(1):36.
87	NN Shah, DM Loeb, H Khuu, et al. Induction of immune response after allogeneic wilms' tumor 1 dendritic cell vaccination and donor lymphocyte infusion in patients with hematologic malignancies and post-transplantation relapse. Biol Blood Marrow Transplant. 2016;22(12):2149-2154.
88	PY Wen, DA Reardon, TS Armstrong, et al. A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma. Clin Cancer Res. 2019;25(19):5799-5807.
89	Z Ding, Q Li, R Zhang, et al. Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer. Signal Transduct Target Ther. 2021;6(1):26.
90	A Harari, M Graciotti, M Bassani-Sternberg, LE Kandalaft. Antitumour dendritic cell vaccination in a priming and boosting approach. Nat Rev Drug Discov. 2020;19(9):635-652.
91	F Veglia, E Sanseviero, DI Gabrilovich. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485-498.
92	A Grover, E Sanseviero, E Timosenko, DI Gabrilovich. Myeloid-derived suppressor cells: a propitious road to clinic. Cancer Discov. 2021;11(11):2693-2706.
93	Z Chen, R Yuan, S Hu, W Yuan, Z Sun. Roles of the exosomes derived from myeloid-derived suppressor cells in tumor immunity and cancer progression. Front Immunol. 2022;13:817942.
94	F Veglia, M Perego, D Gabrilovich. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108-119.
95	H Sui, S Dongye, X Liu, et al. Immunotherapy of targeting MDSCs in tumor microenvironment. Front Immunol. 2022;13:990463.
96	M Liu, J Zhou, X Liu, et al. Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma. Gut. 2020;69(2):365-379.
97	Y Gao, H Xu, N Li, et al. Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression. Cell Commun Signal. 2020;18(1):106.
98	M Jiang, W Zhang, R Zhang, et al. Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer. Oncogene. 2020;39(24):4681-4694.
99	W Qiu, X Guo, B Li, et al. Exosomal miR-1246 from glioma patient body fluids drives the differentiation and activation of myeloid-derived suppressor cells. Mol Ther. 2021;29(12):3449-3464.
100	F Gao, Q Xu, Z Tang, et al. Exosomes derived from myeloid-derived suppressor cells facilitate castration-resistant prostate cancer progression via S100A9/circMID1/miR-506-3p/MID1. J Transl Med. 2022;20(1):346.
101	J-H Zhou, Z-X Yao, Z Zheng, et al. G-MDSCs-derived exosomal miRNA-143-3p promotes proliferation via targeting of ITM2B in lung cancer. OncoTargets and Therapy. 2020;13:9701-9719.
102	Y Wang, K Yin, J Tian, et al. Granulocytic myeloid-derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9. Adv Sci (Weinh). 2019;6(18):1901278.
103	X Xiang, A Poliakov, C Liu, et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer. 2009;124(11):2621-2633.
104	Y Qi, C Jin, W Qiu, et al. The dual role of glioma exosomal microRNAs: glioma eliminates tumor suppressor miR-1298-5p via exosomes to promote immunosuppressive effects of MDSCs. Cell Death Dis. 2022;13(5):426.
105	P Gu, M Sun, L Li, et al. Breast tumor-derived exosomal MicroRNA-200b-3p promotes specific organ metastasis through regulating CCL2 expression in lung epithelial cells. Front Cell Dev Biol. 2021;9:657158.
106	X Jia, J Xi, B Tian, et al. The tautomerase activity of tumor exosomal MIF promotes pancreatic cancer progression by modulating MDSC differentiation. Cancer Immunol Res. 2023;12(1):72-90.
107	Q Zhao, L Huang, G Qin, et al. Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma. Cancer Lett. 2021;518:35-48.
108	X Li, J Zhong, X Deng, et al. Targeting myeloid-derived suppressor cells to enhance the antitumor efficacy of immune checkpoint blockade therapy. Front Immunol. 2021;12:754196.
109	L Cassetta, JW Pollard. Tumor-associated macrophages. Curr Biol. 2020;30(6):R246-R248.
110	Y Pan, Y Yu, X Wang, T Zhang. Corrigendum: tumor-associated macrophages in tumor immunity. Front Immunol. 2021;12:775758.
111	X Dai, L Lu, S Deng, et al. USP7 targeting modulates anti-tumor immune response by reprogramming tumor-associated macrophages in lung cancer. Theranostics. 2020;10(20):9332-9347.
112	X Xiang, J Wang, D Lu, X Xu. Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther. 2021;6(1):75.
113	AN Chamseddine, T Assi, O Mir, S Chouaib. Modulating tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors: a TAM-pting approach. Pharmacol Ther. 2022;231:107986.
114	Y Wang, D Wang, L Yang, Y Zhang. Metabolic reprogramming in the immunosuppression of tumor-associated macrophages. Chin Med J (Engl). 2022;135(20):2405-2416.
115	S Zhao, Y Mi, B Guan, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13(1):156.
116	D Wang, X Wang, M Si, et al. Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages. Cancer Lett. 2020;474:36-52.
117	Y Shou, X Wang, C Chen, et al. Exosomal miR-301a-3p from esophageal squamous cell carcinoma cells promotes angiogenesis by inducing M2 polarization of macrophages via the PTEN/PI3K/AKT signaling pathway. Cancer Cell Int. 2022;22(1):153.
118	L Xin, Y Wu, C Liu, et al. Exosome-mediated transfer of lncRNA HCG18 promotes M2 macrophage polarization in gastric cancer. Mol Immunol. 2021;140:196-205.
119	ZX Liang, HS Liu, FW Wang, 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(11):829.
120	J Chen, Z Lin, L Liu, et al. GOLM1 exacerbates CD8(+) T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages. Signal Transduct Target Ther. 2021;6(1):397.
121	J Lan, L Sun, F Xu, et al. M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer. Cancer Res. 2019;79(1):146-158.
122	X Yang, S Cai, Y Shu, et al. Exosomal miR-487a derived from m2 macrophage promotes the progression of gastric cancer. Cell Cycle. 2021;20(4):434-444.
123	Y Yang, Z Guo, W Chen, et al. M2 macrophage-derived exosomes promote angiogenesis and growth of pancreatic ductal adenocarcinoma by targeting E2F2. Mol Ther. 2021;29(3):1226-1238.
124	K Wei, Z Ma, F Yang, et al. M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer Lett. 2022;526:205-216.
125	P Zheng, Q Luo, W Wang, et al. Tumor-associated macrophages-derived exosomes promote the migration of gastric cancer cells by transfer of functional Apolipoprotein E. Cell Death Dis. 2018;9(4):434.
126	L Wang, X Yi, X Xiao, Q Zheng, L Ma, B Li. Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression. Cell Mol Biol Lett. 2022;27(1):106.
127	ZG Fridlender, J Sun, S Kim, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16(3):183-194.
128	ME Shaul, L Levy, J Sun, et al. Tumor-associated neutrophils display a distinct N1 profile following TGFbeta modulation: a transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology. 2016;5(11):e1232221.
129	AC Mihaila, L Ciortan, RD Macarie, et al. Transcriptional profiling and functional analysis of N1/N2 neutrophils reveal an immunomodulatory effect of S100A9-Blockade on the pro-inflammatory N1 subpopulation. Front Immunol. 2021;12:708770.
130	AC Pena-Romero, E Orenes-Pinero. Dual effect of immune cells within tumour microenvironment: pro- and anti-tumour effects and their triggers. Cancers (Basel). 2022;14(7):1681.
131	R Xue, Q Zhang, Q Cao, et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature. 2022;612(7938):141-147.
132	J Michaeli, ME Shaul, I Mishalian, et al. Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFalpha and NO-dependent mechanism, promoting a tumor-supportive environment. Oncoimmunology. 2017;6(11):e1356965.
133	A Tyagi, S-Y Wu, S Sharma, et al. Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness and metabolism in lung cancer metastasis. Oncogene. 2022;41(22):3079-3092.
134	B Ou, Y Liu, Z Gao, et al. Senescent neutrophils-derived exosomal piRNA-17560 promotes chemoresistance and EMT of breast cancer via FTO-mediated m6A demethylation. Cell Death Dis. 2022;13(10):905.
135	H Zhao, L Wu, G Yan, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021;6(1):263.
136	MT Masucci, M Minopoli, S Del Vecchio, MV Carriero. The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Front Immunol. 2020;11:1749.
137	ML De Meo, JD Spicer. The role of neutrophil extracellular traps in cancer progression and metastasis. Semin Immunol. 2021;57:101595.
138	LY Yang, Q Luo, L Lu, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020;13(1):3.
139	A Shang, C Gu, C Zhou, et al. Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression. Cell Commun Signal. 2020;18(1):52.
140	J Zhang, C Ji, H Zhang, et al. Engineered neutrophil-derived exosome-like vesicles for targeted cancer therapy. Sci Adv. 2022;8(2):eabj8207.
141	X Chen, E Song. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 2019;18(2):99-115.
142	J Gu, H Qian, L Shen, et al. Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-beta/Smad pathway. PLoS One. 2012;7(12):e52465.
143	X Ning, H Zhang, C Wang, X Song. Exosomes released by gastric cancer cells induce transition of pericytes into cancer-associated fibroblasts. Med Sci Monit. 2018;24:2350-2359.
144	Y Zhou, H Ren, B Dai, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J Exp Clin Cancer Res. 2018;37(1):324.
145	Z Li, C Sun, Z Qin. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming. Theranostics. 2021;11(17):8322-8336.
146	X Xiang, YR Niu, ZH Wang, LL Ye, WB Peng, Q Zhou. Cancer-associated fibroblasts: vital suppressors of the immune response in the tumor microenvironment. Cytokine Growth Factor Rev. 2022;67:35-48.
147	C Li, AF Teixeira, HJ Zhu. Ten Dijke P. Cancer associated-fibroblast-derived exosomes in cancer progression. Mol Cancer. 2021;20(1):154.
148	A Rai, DW Greening, M Chen, R Xu, H Ji, RJ Simpson. Exosomes derived from human primary and metastatic colorectal cancer cells contribute to functional heterogeneity of activated fibroblasts by reprogramming their proteome. Proteomics. 2019;19(8):e1800148.
149	D Wang, X Wang, Y Song, 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(4):380.
150	T Fang, H Lv, G Lv, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9(1):191.
151	Y Mo, LL Leung, CSL Mak, et al. Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis. Mol Cancer. 2023;22(1):4.
152	H Yang, B Sun, L Fan, et al. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics. 2022;12(7):3104-3130.
153	L Shi, Z Wang, X Geng, Y Zhang, Z Xue. Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells in vitro and in vivo. Aging (Albany NY). 2020;12(9):8549-8564. Aging (Albany NY).
154	G Xu, B Zhang, J Ye, et al. Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression. Int J Biol Sci. 2019;15(11):2320-2329.
155	Y Jin, Q Meng, B Zhang, et al. Cancer-associated fibroblasts-derived exosomal miR-3656 promotes the development and progression of esophageal squamous cell carcinoma via the ACAP2/PI3K-AKT signaling pathway. Int J Biol Sci. 2021;17(14):3689-3701.
156	JL Hu, W Wang, XL Lan, et al. CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Mol Cancer. 2019;18(1):91.
157	B Chen, Y Sang, X Song, et al. Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes breast cancer cell proliferation and metastasis through targeting USP28. Theranostics. 2021;11(8):3932-3947.
158	J-T Fan, Z-Y Zhou, Y-L Luo, et al. Exosomal lncRNA NEAT1 from cancer-associated fibroblasts facilitates endometrial cancer progression via miR-26a/b-5p-mediated STAT3/YKL-40 signaling pathway. Neoplasia. 2021;23(7):692-703.
159	K Yang, J Zhang, C Bao. Exosomal circEIF3K from cancer-associated fibroblast promotes colorectal cancer (CRC) progression via miR-214/PD-L1 axis. BMC Cancer. 2021;21(1):933.
160	HW Zhang, Y Shi, JB Liu, et al. Cancer-associated fibroblast-derived exosomal microRNA-24-3p enhances colon cancer cell resistance to MTX by down-regulating CDX2/HEPH axis. J Cell Mol Med. 2021;25(8):3699-3713.
161	X Deng, H Ruan, X Zhang, et al. Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells. Int J Cancer. 2020;146(6):1700-1716.
162	Y Duan, X Zhang, H Ying, et al. Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix. Oncogene. 2023;42(25):2061-2073.
163	R Sakemura, M Hefazi, EL Siegler, et al. Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma. Blood. 2022;139(26):3708-3721.
164	S Qiu, L Xie, C Lu, et al. Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis. J Exp Clin Cancer Res. 2022;41(1):296.
165	D Fukumura, J Kloepper, Z Amoozgar, DG Duda, RK Jain. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15(5):325-340.
166	P Carmeliet. VEGF as a key mediator of angiogenesis in cancer. Oncology. 2005;69(3):4-10. Suppl.
167	S Li, J Li, H Zhang, et al. Gastric cancer derived exosomes mediate the delivery of circRNA to promote angiogenesis by targeting miR-29a/VEGF axis in endothelial cells. Biochem Biophys Res Commun. 2021;560:37-44.
168	M Xie, T Yu, X Jing, et al. Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation. Mol Cancer. 2020;19(1):112.
169	X Xue, J Huang, K Yu, et al. YB-1 transferred by gastric cancer exosomes promotes angiogenesis via enhancing the expression of angiogenic factors in vascular endothelial cells. BMC Cancer. 2020;20(1):996.
170	Z Huang, Y Feng. Exosomes derived from hypoxic colorectal cancer cells promote angiogenesis through Wnt4-induced beta-catenin signaling in endothelial cells. Oncol Res. 2017;25(5):651-661.
171	Q He, A Ye, W Ye, et al. Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1. Cell Death Dis. 2021;12(6):576.
172	HS Venkatesh, W Morishita, AC Geraghty, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573(7775):539-545.
173	SM Gysler, R Drapkin. Tumor innervation: peripheral nerves take control of the tumor microenvironment. J Clin Invest. 2021;131(11):e147276.
174	M Amit, H Takahashi, MP Dragomir, et al. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature. 2020;578(7795):449-454.
175	D Hanahan, M Monje. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell. 2023;41(3):573-580.
176	C Anastasaki, J Mo, J-K Chen, et al. Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1. Nat Commun. 2022;13(1):2785.
177	S Deborde, L Gusain, A Powers, et al. Reprogrammed Schwann cells organize into dynamic tracks that promote pancreatic cancer invasion. Cancer Discov. 2022;12(10):2454-2473.
178	D Jiang, F Gong, X Ge, et al. Neuron-derived exosomestransmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes. J Nanobiotechnol. 2020;18(1):105.
179	L-L Xu, J-Q Xie, J-J Shen, M-D Ying, X-Z Chen. Neuron-derived exosomes mediate sevoflurane-induced neurotoxicity in neonatal mice via transferring lncRNA Gas5 and promoting M1 polarization of microglia. Acta Pharmacol Sin. 2023;45(2):298-311.
180	X Xu, Z Li, H Zuo, H Chen, Y Gui. Mesenchymal stem cell-derived exosomes altered neuron cholesterol metabolism via Wnt5a-LRP1 axis and alleviated cognitive impairment in a progressive Parkinson's disease model. Neurosci Lett. 2022;787:136810.
181	S Jin, X Chen, Y Tian, R Jarvis, V Promes, Y Yang. Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation. Nat Commun. 2023;14(1):5150.
182	R Spelat, N Jihua, CA Sánchez Trivi?o, et al. The dual action of glioma-derived exosomes on neuronal activity: synchronization and disruption of synchrony. Cell Death Dis. 2022;13(8):705.
183	R Sedano, D Cabrera, A Jimenez, et al. Immunotherapy for cancer: common gastrointestinal, liver, and pancreatic side effects and their management. Am J Gastroenterol. 2022;117(12):1917-1932.
184	N Zhuo, C Liu, Q Zhang, et al. Characteristics and prognosis of acquired resistance to immune checkpoint inhibitors in gastrointestinal cancer. JAMA Netw Open. 2022;5(3):e224637.
185	Q Wang, X Shen, G Chen, J Du. How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: from mechanisms to translation. Int J Cancer. 2023;153(4):709-722.
186	Q Tang, S Yang, G He, et al. Tumor-derived exosomes in the cancer immune microenvironment and cancer immunotherapy. Cancer Lett. 2022;548:215823.
187	C Wang, X Huang, Y Wu, J Wang, F Li, G Guo. Tumor cell-associated exosomes robustly elicit anti-tumor immune responses through modulating dendritic cell vaccines in lung tumor. Int J Biol Sci. 2020;16(4):633-643.
188	FG Kugeratski, R Kalluri. Exosomes as mediators of immune regulation and immunotherapy in cancer. FEBS J. 2021;288(1):10-35.
189	P Neviani, PM Wise, M Murtadha, et al. Natural killer–derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms. Cancer Res. 2019;79(6):1151-1164.
190	W-J Zhou, J Zhang, F Xie, et al. CD45RO-CD8+ T cell-derived exosomes restrict estrogen-driven endometrial cancer development via the ERβ/miR-765/PLP2/Notch axis. Theranostics. 2021;11(11):5330-5345.
191	J Wen, Y Chen, C Liao, et al. Engineered mesenchymal stem cell exosomes loaded with miR-34c-5p selectively promote eradication of acute myeloid leukemia stem cells. Cancer Lett. 2023;575:216407.
192	G Liang, Y Zhu, DJ Ali, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J Nanobiotechnology. 2020;18(1):10.
193	D Lin, H Zhang, R Liu, et al. iRGD-modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation. Mol Oncol. 2021;15(12):3430-3446.
194	X Li, Q Yu, R Zhao, et al. Designer exosomes for targeted delivery of a novel therapeutic cargo to enhance sorafenibmediated ferroptosis in hepatocellular carcinoma. Front Oncol. 2022;12:898156.
195	Z Huang, M Yang, Y Li, F Yang, Y Feng. Exosomes derived from hypoxic colorectal cancer cells transfer wnt4 to normoxic cells to elicit a prometastatic phenotype. Int J Biol Sci. 2018;14(14):2094-2102.
196	L Zhang, Y Lin, S Li, X Guan, X Jiang. In situ reprogramming of tumor-associated macrophages with internally and externally engineered exosomes. Angew Chem Int Ed Engl. 2023;62(11):e202217089.
197	S Hu, J Ma, C Su, et al. Engineered exosome-like nanovesicles suppress tumor growth by reprogramming tumor microenvironment and promoting tumor ferroptosis. Acta Biomater. 2021;135:567-581.
198	C Gong, X Zhang, M Shi, et al. Tumor exosomes reprogrammed by low pH are efficient targeting vehicles for smart drug delivery and personalized therapy against their homologous tumor. Adv Sci (Weinh). 2021;8(10):2002787.
199	S Wang, F Li, T Ye, et al. Macrophage-tumor chimeric exosomes accumulate in lymph node and tumor to activate the immune response and the tumor microenvironment. Sci Transl Med. 2021;13(615):eabb6981.
200	W Fu, C Lei, S Liu, et al. CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity. Nat Commun. 2019;10(1):4355.
201	J Lin, N Huang, M Li, et al. Dendritic cell-derived exosomes driven drug co-delivery biomimetic nanosystem for effective combination of malignant melanoma immunotherapy and gene therapy. Drug Des Devel Ther. 2023;17:2087-2106.
202	L Cheng, X Zhang, J Tang, Q Lv, J Liu. Gene-engineered exosomes-thermosensitive liposomes hybrid nanovesicles by the blockade of CD47 signal for combined photothermal therapy and cancer immunotherapy. Biomaterials. 2021;275:120964.
203	M Mohammadi, H Zargartalebi, R Salahandish, R Aburashed, K Wey Yong, A Sanati-Nezhad. Emerging technologies and commercial products in exosome-based cancer diagnosis and prognosis. Biosens Bioelectron. 2021;183:113176.
204	T Guo, XH Tang, XY Gao, et al. A liquid biopsy signature of circulating exosome-derived mRNAs, miRNAs and lncRNAs predict therapeutic efficacy to neoadjuvant chemotherapy in patients with advanced gastric cancer. Mol Cancer. 2022;21(1):216.
205	J Zhang, M Guan, C Ma, et al. Highly effective detection of exosomal miRNAs in plasma using liposome-mediated transfection CRISPR/Cas13a. ACS Sensors. 2023;8(2):565-575.
206	Z Yu, Y Yang, W Fang, P Hu, Y Liu, J Shi. Dual tumor exosome biomarker co-recognitions based nanoliquid biopsy for the accurate early diagnosis of pancreatic cancer. ACS Nano. 2023;17(12):11384-11395.
207	MA Morse, J Garst, T Osada, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005;3(1):9.
208	B Besse, M Charrier, V Lapierre, et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. OncoImmunology. 2015;5(4):e1071008.
209	B Escudier, T Dorval, N Chaput, 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.
210	S Dai, D Wei, Z Wu, et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther. 2008;16(4):782-790.
211	M Narita, T Kanda, T Abe, et al. Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine. Int J Oncol. 2015;46(4):1699-1709.
212	Y Tang, Y Zhao, X Song, X Song, L Niu, L Xie. Tumor-derived exosomal miRNA-320d as a biomarker for metastatic colorectal cancer. J Clin Lab Anal. 2019;33(9):e23004.
213	Y Shi, Z Wang, X Zhu, et al. Exosomal miR-1246 in serum as a potential biomarker for early diagnosis of gastric cancer. Int J Clin Oncol. 2020;25(1):89-99.
214	X Wang, T Qian, S Bao, et al. Circulating exosomal miR-363-5p inhibits lymph node metastasis by downregulating PDGFB and serves as a potential noninvasive biomarker for breast cancer. Mol Oncol. 2021;15(9):2466-2479.
215	Y Wu, J Wei, W Zhang, M Xie, X Wang, J Xu. Serum exosomal miR-1290 is a potential biomarker for lung adenocarcinoma. Onco Targets Ther. 2020;13:7809-7818.
216	M Liu, F Mo, X Song, et al. Exosomal hsa-miR-21-5p is a biomarker for breast cancer diagnosis. PeerJ. 2021;9:e12147.
217	C Li, Y Lv, C Shao, et al. Tumor-derived exosomal lncRNA GAS5 as a biomarker for early-stage non-small-cell lung cancer diagnosis. J Cell Physiol. 2019;234(11):20721-20727.
218	A Patel, S Patel, P Patel, D Mandlik, K Patel, V Tanavde. Salivary exosomal miRNA-1307-5p predicts disease aggressiveness and poor prognosis in oral squamous cell carcinoma patients. Int J Mol Sci. 2022;23(18):10639.
219	J Liu, J Yoo, JY Ho, et al. Plasma-derived exosomal miR-4732-5p is a promising noninvasive diagnostic biomarker for epithelial ovarian cancer. J Ovarian Res. 2021;14(1):59.
220	S Chen, Y Mao, W Chen, et al. Serum exosomal miR-34a as a potential biomarker for the diagnosis and prognostic of hepatocellular carcinoma. J Cancer. 2022;13(5):1410-1417.
221	Y Xie, J Li, P Li, et al. RNA-Seq profiling of serum exosomal circular RNAs reveals Circ-PNN as a potential biomarker for human colorectal cancer. Front Oncol. 2020;10:982.
222	B Pan, J Qin, X Liu, et al. Identification of serum exosomal hsa-circ-0004771 as a novel diagnostic biomarker of colorectal cancer. Front Genet. 2019;10:1096.
223	K Li, Y Lin, Y Luo, et al. A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study. Mol Cancer. 2022;21(1):21.
224	Y Lin, H Dong, W Deng, et al. Evaluation of salivary exosomal chimeric GOLM1-NAA35 RNA as a potential biomarker in esophageal carcinoma. Clin Cancer Res. 2019;25(10):3035-3045.
225	Z Dong, X Sun, J Xu, et al. Serum membrane type 1-matrix metalloproteinase (MT1-MMP) mRNA protected by exosomes as a potential biomarker for gastric cancer. Med Sci Monit. 2019;25:7770-7783.
226	W Guo, Y Cai, X Liu, et al. Single-exosome profiling identifies ITGB3+ and ITGAM+ exosome subpopulations as promising early diagnostic biomarkers and therapeutic targets for colorectal cancer. Research (Wash D C). 2023;6:0041.
227	Y Shen, M Li, L Liao, S Gao, Y Wang. Plasma exosome-derived connexin43 as a promising biomarker for melanoma patients. BMC Cancer. 2023;23(1):242.
228	X Zhao, D Wu, X Ma, J Wang, W Hou, W Zhang. Exosomes as drug carriers for cancer therapy and challenges regarding exosome uptake. Biomed Pharmacother. 2020;128:110237.
229	L Huang, Y Rong, X Tang, et al. Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer. Mol Cancer. 2022;21(1):45.
230	YS Ma, XL Yang, R Xin, JB Liu, D Fu. Power and promise of exosomes as clinical biomarkers and therapeutic vectors for liquid biopsy and cancer control. Biochim Biophys Acta Rev Cancer. 2021;1875(1):188497.
231	RM Johnstone, M Adam, JR Hammond, L Orr, C Turbide. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262(19):9412-9420.
232	G Raposo, HW Nijman, W Stoorvogel, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161-1172.
233	C Théry, A Regnault, J Garin, et al. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol. 1999;147(3):599-610.
234	H Valadi, K Ekstr?m, A Bossios, M Sj?strand, JJ Lee, JO L?tvall. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654-659.
235	A Hoshino, B Costa-Silva, TL Shen, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329-335.