Skip to main content

Exosomal miRNAs in tumor microenvironment


Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping.


TME is a complex ecosystem and an important player in all stages of tumorigenesis. TME consists of cancer cells, cancer-associated fibroblasts (CAFs), endothelial cells, immune cells, extracellular matrix (ECM), microvessels, and biomolecules infiltrated [1,2,3,4,5]. Compared with the normal internal environment, TME is more prominently characterized by hypoxia. Hypoxia caused by rapid appreciation of tumor cells leads to release of matrix metalloproteinases (MMPs), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and other stimulating factors. Reshaping TME provides a niche for interaction between tumor cells and surrounding fibroblasts, endothelial cells, and immune cells [4, 6,7,8,9]. These cells interact with tumor cells through TME to induce a variety of biological events, such as appreciation, migration, angiogenesis, immunosuppression, and drug resistance for tumor development [10,11,12,13,14].

MicroRNAs (miRNAs) are a class of short ncRNAs with 19-25 nucleotides in length [15]. Through regulating gene expression, miRNAs regulate a variety of important biological functions, such as proliferation, apoptosis, differentiation, migration, invasion and drug resistance. Genetic or epigenetic changes in cancer cells can induce abnormal expression of miRNAs, thus causing abnormal expression of their target genes [16,17,18,19,20,21]. miRNAs function through 6-7 base complementary binding to target mRNA and inhibition of target gene expression at the level of protein [22,23,24]. From the literature, miRNAs can work as oncogenes to promote the formation and biological changes of TME [25,26,27,28]. For example, miR-9 and miR-200s induce normal fibroblasts (NFs) in TME to transform into CAFs and promote tumor metastasis [29, 30], miR-526b and miR-655 promote angiogenesis and lymphangiogenesis in TME [31], and miR-340-5p and miR-561 induce formation of immunosuppressive microenvironment [32, 33]. How these biologically active miRNAs are transmitted and function in cells and TME is an important breakthrough in the study of TME.

Recently, exosomes are considered to be the key mediators responsible for the heterogeneity of the TME and carry biologically active cargos, such as protein, metabolites, nucleic acids (e.g. ncRNAs), to shuttle between tumor cells and TME, thereby affecting tumor development [34,35,36,37]. Among the biologically active substances, tumor-derived exosomal miRNAs can induce TME heterogeneity while changes in TME promote tumor progression. This paradigm, similar to a positive feedback loop, makes the uncontrollable growth of the tumor [38,39,40,41,42,43]. In this article we updated the interaction of exosomal miRNAs and TME.

The overview of microenvironment and exosomes in cancer

The components of tumor microenvironment

Growth, metastasis and treatment resistance of tumors are inseparable from the support of TME, a dynamic ecosystem containing multiple cell types and non-cellular components. Some of the basic biological behavioral features of tumors, such as proliferation, migration, invasion, apoptosis inhibition, immune evasion, angiogenesis, and metabolic reprogramming are all affected by TME. The complex communication network in TME is the basis for the regulation of these biological functions, including autocrine and paracrine. Exocrine-mediated communication is an important emerging pathway in paracrine signal transduction [2].

Non-tumor cells in TME, such as fibroblasts, endothelial cells and immune cells, are affected by tumor-related active substances, and their original cellular functions undergo tumor-like changes, constantly adapt to new environments and promote tumor growth. Due to the influence of TME, NFs are activated into CAFs. CAFs are the most abundant stromal cells in TME, producing an ECM that differs from normal ECM in terms of stiffness and alignment, which support tumor cells migration [9]. Hypoxia in TME causes tumor to secrete angiogenic factors to act on endothelial cells and promote angiogenesis [44, 45]. The immune cells in TME show diversity, and they block the immune response. The inflammatory molecules around the tumor cells also cause the system to fail to recognize and eliminate cancer cells [38, 46, 47]. These make TME a complex heterogeneous environment and often leads to an uncontrollable trend in the development of tumors [48, 49].

The biosynthesis and function of extracellular vesicles and exosomes

Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles (40-1000nm in diameter) released by cells or detached from the plasma membrane [50, 51]. EVs are generally divided into two categories: ectosomes and exosomes. Ectosomes are vesicles formed from the plasma membrane sprouting outwards, including microvesicles, microparticles and large vesicles with a size range of 50-1000nm in diameter. Exosomes are small extracellular vesicle (sEVs) in a size range of 40-160nm in diameter with an endosomal origin. EVs have biological activities and mediate intercellular communication [36]. During tumor progression, EVs derived from different cells (tumor cells, stromal cells, immune cells, etc.) play an important role and participate in the formation of TME [44, 52,53,54].

In this review, we mainly focused on the exosomes. However, because of absence of strict standards for exosome isolation and purification methods, the International Society for Extracellular Vesicles encouraged researchers to establish minimum requirements and strictly control the integrity, size, molecular cargo, and functionality of the vesicle population [38, 55,56,57], so that we narrowed the research of exosomes based on the widely accepted methods. Exosomes are small extracellular vesicles (40-160 nm in diameter) formed by dynamic exocytosis [58,59,60]. Exosomes originate from the luminal cavity or early intracellular bodies in the circulation pathway of the plasma membrane. These membranes or early intracellular bodies will sag inward to form intraluminal vesicles (ILV), which will further develop into multivesicular bodies (MVB) [61, 62]. In general, multivesicular bodies are fused with lysosomes to be degraded, but some multivesicular bodies are fused to the cell surface under the traction of intracellular molecular motors and eventually secreted outside the cell, which called exosomes [36, 63].

Exosomes are involved in the biology of many diseases. Exosomes can regulate the immune response and inflammation, possibly through transfer and presentation of antigen peptides, to induce expression of inflammatory genes in recipient cells [64, 65]. In metabolism and cardiovascular diseases, exosomes induce metabolic disorders in adipocytes and islet cells [66, 67]. Exosomes may impair the formation of neurotoxic oligomers and promote neurodegeneration [68,69,70]. More importantly, exosomes are associated with tumor growth, angiogenesis, metastasis, sensitivity to chemotherapy, and immune evasion [47, 71, 72].

miRNAs sorting to exosomes

Exosomes contain a variety of biologically active molecules, such as proteins, lipids and nucleic acids. miRNAs are one of them and play an important role in intercellular cellular transport and signal transduction [73,74,75]. Exosomes can transfer metabolites and promote communication between different cells through the exchange of exosomal miRNAs, and then play an immune response, tumor microenvironment remodeling and tumor metastasis during tumor progression [38, 76,77,78]. Many reports indicate that exosomes affect the biology of recipient cells by transferring miRNAs from donor cells to recipient cells, but the mechanism of how exosomes sorting miRNAs has not been thoroughly solved. According to exosomes database (, 2838 miRNAs are listed in the latest update. Among the 2588 annotated miRNAs in the human genome, 593 miRNAs have been detected in exosomes [79]. Four potential mechanisms for sorting miRNAs into exosomes were proposed. The neural sphingomyelinase 2 (nSMase2) was the first molecule found to be linked with miRNAs packaging into exosomes. Overexpression of nSMase2 leads to an increased number of miRNAs loaded into exosomes. This suggests that the neural sphingomyelinase 2 (nSMase2)-dependent pathway is associated with the sorting of exosomal miRNAs [80]. The second is based on the control of the sumoylated form of heterogeneous nuclear ribonucleoprotein (hnRNP). Sumoylated hnRNPA2B1 controls the sorting of exosomal miRNAs by recognizing the GGAG and GGCU base sequence of the 3 ’end region of miRNAs [81, 82]. The third is that most exosomal miRNAs isolated from urine or B cells were uridylated at 3 ′ ends. The sorting of miRNAs to ILV may also require hydrophobic modification and GGAG base sequence at 3 ′ end of the miRNAs. This indicates that the 3 ’ends of miRNAs may be involved in directing miRNAs into exosomes [83, 84]. Finally, there are reports that Argonaute proteins (functional carriers of miRNAs) are related to the selection of exosomal miRNAs. Knocking out Argonaute 2 (Ago2) reduces the contents of certain exosomal miRNAs, such as miR-142-3p, miR-150, and miR-451 [85, 86]. In summary, some specific protein complexes and miRNAs own structural characteristics have affects the miRNAs' transfer to exosomes, but the complete sorting mechanism and process have not yet been elucidated and need further exploration.

The role of exosomal miRNAs in TME

During the progression of the tumor, primary tumor-derived exosomal miRNAs can be transferred to non-malignant cells in the tumor microenvironment to induce heterogeneity [50, 87,88,89]. At the same time, with the changes in biological activity of non-malignant cells in the tumor microenvironment, non-malignant cells can also secrete exosomal miRNAs to further regulate tumor cells or other microenvironmental components [40, 90]. In most studies, the stromal cell receptors of cancer-derived exosomal miRNAs are cancer-associated fibroblasts (CAFs), endothelial cells and immune cells dynamically regulate each other in TME. Exosomal miRNAs on the heterogeneity of TME is mainly reflected in the fact that exosomal miRNAs can activate cancer-associated fibroblasts and thus reshape ECM, which is beneficial to the spread of tumor cells. Exosomal miRNAs promote endothelial cells to form tubes, and the formation of abundant vascular networks is conducive to the metabolism and survival of tumor cells. Exosomal miRNAs also mediate inflammatory cell infiltration and immune escape, which is conducive to colonization and proliferation of tumor cells. Through these macroscopic effects, exosomal miRNAs can make TME more suitable for tumor development [91]. Herein, we focused on the roles of exosomal miRNAs in following aspects.

Reshaping ECM to promote tumor progression

Extracellular matrix (ECM) is composed of protein and carbohydrates, with the functions of connection, support, water retention, anti-stress and protection. ECM supports the basic life activities of cells, such as proliferation, differentiation, and migration [92, 93]. However, tumors are often accompanied by dysfunction of ECM. Tumor development is a complex process involving dynamic interactions between malignant cells and their surrounding stroma composed of cells and non-cellular components. Within the stromal, fibroblasts represent not only the major cell types, but also the main source of extracellular matrix (ECM) and soluble factors [94, 95]. Normal fibroblasts exert multiple inhibitory functions against cancer-initiating and metastasis through direct cell-cell contact, paracrine signaling, and ECM integrity [96]. However, tumor-derived exosomal miRNAs can trigger a series of tumor-promoting signals, inducing normal fibroblasts (NFs) transformation into CAFs, which changes the original ECM physiological state, thus creating the optimal niche for the widespread growth of cancer cells [96, 97].

In tumors, tumor cell-derived exosomal miRNAs are highly diverse and are capable of differentiating NFs into CAFs through a variety of signaling pathways. Exosomal miRNAs from cancer cells elicit a parenchymal signaling response at the receptor site and effectively inducing fibroblast activation, such as α-smooth muscle actin (α-SMA), fibroblast growth factor 2 (FGF2) and fibroblast activating protein (FAP) expression [98,99,100]. Matrix composed of CAFs is conducive to the proliferation and migration of tumor cells. In ovarian cancer, the cancer-related exosomal miR-124 targets sphingosine kinase 1 (SPHK1) and upregulates α-SMA and FAP, which differentiates NFs into CAFs and regulates CAFs migration and invasion [101, 102]. High expression of exosomal miR-27b-3p and miR-214-3p in myeloma cells triggers proliferation and apoptotic resistance of bone marrow fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways. At the same time, miR-27-3p and miR-214-3p were up-regulated in fibroblasts co-cultured with myeloma, and activated expression of fibroblast activation markers α-SMA and FAP. The biological behavior of bone marrow fibroblasts is programmed to alter the myeloma microenvironment [103, 104]. Exosomal miRNAs in digestive system tumors also reshaped ECM in adjacent sites and promote tumor progression. Exosomal miR-27a derived from gastric cancer (GC) is transported to fibroblasts, and thus results in decreased expression of CSRP2, enhanced expression of α-SMA, and differentiation of fibroblasts into CAFs [105]. Exosomal miR-10b secreted by colorectal cancer cells can be transferred to fibroblasts, where it inhibits PIK3CA expression and PI3K/Akt/mTOR pathway activity, promote expression of TGF-β and α-SMA, and enable fibroblasts to acquire the characteristics of CAFs [106, 107]. These changes promote the proliferation, migration and invasion of tumor cells. Exosomal miRNAs have found similar effects in colorectal cancer (CRC). Exosomal miR-2149-5p, miR-6737-5p, and miR-6819-5p can inhibit the expression of TP53 in fibroblasts to promote tumor proliferation [108].

In addition, changes in ECM also affect angiogenesis, inflammatory response, and metabolic reprogramming. Phenomenon was shown in melanoma where highly expressed exosomal miR-155 inhibits the expression of SOCS1, activates the JAK2/STAT3 pathway, up-regulates the expression of FGF2, VEGFA and MMP9 in CAFs, and promotes the formation of blood vessels in the tumor [109, 110]. In hepatocarcinoma (HCC), exosomal miR-21 is transferred to CAFs, directly targeting PTEN to activate PDK1/Akt signaling, up-regulating VEGF, MMP2, MMP9, bFGF, and TGF-beta and thus promoting angiogenesis [111, 112]. Exosomal miR-1247 targets B4GALT3 and activates the beta1-integrin-NF-kappaB signaling pathway, which activates CAFs to secrete the inflammatory cytokines IL-6 and IL-8 and induce inflammatory infiltration [113]. Exosomal miR-9 and miR-105 are derived from breast cancer; the former promotes the activation of NFs into CAFs by affecting MMP1, EFEMP1 and COL1A1 [30], and the latter activates MYC signal transduction to induce metabolic reprogramming of CAFs, and adapts CAFs to different metabolic environments, promoting tumor growth [18]. Similar reports include miRNA-142-3p in EVs secreted by lung cancer cells, which promotes the cancer phenotype of lung fibroblasts [114] (Fig. 1 and Table 1).

Fig. 1.

The mechanism of ECM reshaping by exosomal miRNAs . Exosomes secreted by the primary tumor cells are taken up by the receptor NFs, wherein the exosomal miRNAs (miR-155, miR-21, miR-124, etc.) target the proteins (SOCS1, PTEN, SPHK1, etc.) and activate the molecules (FGF2, bFGF, TGF-β, α-SMA, FAP, etc.). These exosomal miRNAs reshape the ECM by inducing the conversion of normal fibroblasts (NFs) into cancer-associated fibroblasts (CAFs).

Table 1 Exosomal miRNAs involved in tumor microenvironments

These researches show that cancer-derived exosomal miRNAs can affect the physiological function of stroma. Conversely, a reciprocal exosomal miRNAs exchange from the stroma to cancer cells also modulates cancer progression. For example, CAFs-derived exosomal miR-148b in the matrix surrounding endometrial cancer can up-regulate DNMT1, leading to changes in EMT-related molecules like E-cadherin, N-cadherin, vimentin, and fibronectin and promoting cancer cell metastasis [65]. CAFs are resistant to cisplatin and deliver exosomal miR-196a, which binds to target CDKN1B and ING5, mediates the expressions of p27, CDK2, CDK4, Cyclin D1 and Cyclin E1 and thus induces cisplatin resistance to cancer cells [115]. CAFs-derived exosomal miR-522 reduces the contents of lipid-ROS in gastric cancer cells by inhibiting the expression of ALOX15, which leads to a decrease in the sensitivity of gastric cancer to chemotherapy [12].

Compared with NFs, CAFs have the characteristics of excessive proliferation and unique cytokines. This not only induces the formation of new blood vessels, but also promotes the entry of immune cells into TME, which greatly changes the physiological function of ECM to support tumor proliferation, metastasis and treatment resistance [116, 117]. However, cells involved in ECM formation are not only fibroblasts, but also chondrocytes, osteoblasts, and certain epithelial cells. Exosomal miRNA remodeling of ECM can also be achieved by affecting the function of these cells. For example, studies have shown that cancer-secreted exosomal miR-940 promotes osteogenic differentiation of mesenchymal cells by targeting ARHGAP1 and FAM134A, and then induces osteogenic phenotypes in the bone metastasis microenvironment and promotes tumor metastasis [118]. But research on the interaction of exosomal miRNAs with these cells is not comprehensive. At the same time, the composition of ECM not only includes collagen (synthesized by fibroblasts, chondrocytes, osteoblasts and certain epithelial cells and secreted outside the cell), but also includes non-collagen glycoproteins, glycans and elastin. Whether exosomal miRNAs reshape ECM by affecting these ingredients remains to be proven.

Promoting angiogenesis to enhance proliferation and migration

Tumor growth depends to a large extent on the metabolism of cancer cells [119]. The disordered distribution of tumor blood vessels and the loss of normal vascular function lead to local hypoxia and impaired nutrient supplies. At the same time, the distance gradient between different vascular beds also leads to the imbalance of drug distribution and absorption [120]. These changes of vascular network promote the formation of internal microenvironment and intratumoral heterogeneity.

The exosomal miRNAs can be taken up by the vascular endothelial cells to change the original distribution and physiological functions of the blood vessels in the microenvironment. Exosomal miRNAs secreted by tumor cells have been reported to promote angiogenesis in TME. In nasopharyngeal carcinoma (NPC), exosomal miR-23a mediates angiogenesis by repressing TSGA10 and phosphorylation of ERK, which enhances tube generation ability of human umbilical vein endothelial cells (HUVECs) in vitro and in vivo [121, 122]. Glioma stem cell-derived exosomal miR-21 stimulates VEGF/p-FLK/VEGFR2 signaling pathway to promote angiogenesis in endothelial cells [123, 124]. The exosomal miR-210-3p secreted by HCC cells is transferred to endothelial cells, targeting SMAD4 and STAT6 to promote angiogenesis, and it is found that the higher miR-210-3p in the serum of HCC patients is positively correlated with the microvessel density in HCC tissues [125]. EVs and sEVs-mediated miRNAs transfer also promotes angiogenesis in TME. In NSCLC, EVs-mediated miR-142-3p transferred to endothelial cells and fibroblasts, inhibiting the expression of TGFβR1, PDGFR-β and p-SMAD2/3 to promote angiogenesis [114]. Human ovarian carcinoma cell line SKOV-3 secretes miR-141-3p in small extracellular vesicles (sEVs), which activates the JAK-STAT3 pathway in endothelial cells and promotes angiogenesis [126]. Besides, exosomal miRNAs that promote angiogenesis can also be derived from other cells. Exosomal miR-100 from human mesenchymal stem cells (MSCs) affects the mTOR/HIF-1α/VEGF signaling axis to promote angiogenesis in breast cancer [127].

The rich vascular network in TME is beneficial to the proliferation and metastasis of cancer cells. Exosomal miR-619-5p inhibits the expression of RCAN1.4, promotes angiogenesis, and facilitates the growth and metastasis of cancer cells [128]. Recent studies have shown that circulating exosomal miR-205 expression is elevated in OC patients and is related to microvessel density, and exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway, and promotes tumor cell proliferation in vitro [129]. Changes in the vascular microenvironment are not only in the number of blood vessels, but also in vascular permeability, adhesion, and ability to form a ring. The colorectal cancer-derived exosomal miR-25-3p can down-regulate KLF2 and KLF4, and KLF2 affects the tube formation ability of HUVECs through the VEGFR2/p-Erk/p-Akt pathway while KLF4 activates ZO-1/Occludin/Claudin5 pathway to affect the growth of the aortic rings, which in turn changes the vascular microenvironment [130, 131]. Under hypoxic conditions, lung cancer cell-derived exosomal miR-23a directly inhibits prolyl hydroxylase 1 and 2 (PHD1 and PHD2) and accumulates HIF-1α in endothelial cells, inducing angiogenesis, and exosomal miR- 23a also inhibits ZO-1, increasing vascular permeability and transendothelial migration of cancer cells [132]. In human glioma, exosomal miR-9 promotes angiogenesis, vascular permeability and adhesion through the MYC/OCT4 pathway [133] (Fig. 2).

Fig. 2.

The mechanism of angiogenesis promoted by exosomal miRNAs. Exosomes secreted by the primary tumor cells are taken up by the receptor endothelial cells, wherein the exosomal miRNAs (miR-23a, miR-25-3p, miR-205, etc.) target the proteins (TSGA10, KLF2, PTEN, etc.) and activate the molecules (VEGFR2, p-AKT, p-ERK, etc.). These exosomal miRNAs promote angiogenesis by regulating the number of local blood vessels and physiological functions.

Exosomal miRNAs influence on vascular network is not only promotion, but sometimes also play an inhibitory effect. Studies have found that exosomal miR-451 acts as a tumor suppressor and targets LPIN1 to induce apoptosis both in HCC cell lines and HUVECs. In addition, miR-451a suppresses HUVECs tube formation and vascular permeability [134]. NPC-derived exosomal miR-9 up-regulates MDK and activates the PDK/Akt signaling pathway to inhibit the formation of endothelial cells. High expression of MDK in NPC tumor samples is positively correlated with microvessel density, revealing the anti-angiogenic effects of exosomal miR-9 in the development of nasopharyngeal carcinoma [135]. Except for tumor-derived exosomal miRNAs, which inhibit angiogenesis, non-tumor cells have similar functions. miR-15a, miR-181b, miR-320c, and miR-874 in EVs released by human liver stem-like cells (HLSCs) possess an anti-tumorigenic effect by inhibiting tumor angiogenesis [136]. According to these reports, it can be found that exosomal miRNAs can regulate the vascular network in TME through multiple signaling pathways, but these molecular mechanisms have not been fully elucidated and need to be explored in the future.

Promoting the formation of immunosuppressive environment

In the TME, immune cells including lymphocytes, dendritic cells, and macrophages, regularly infiltrate tumor tissues and adjacent sites. Through multiple signal transduction pathways mediated by exosomal miRNAs, tumor cells can inhibit the maturation and differentiation of immune cells, thereby creating an immune microenvironment suitable for tumor growth [41, 137, 138]. At the same time, in hypoxia and low nutrient supplies in the microenvironment, tumor cells often secrete metabolic by-products, such as lactic acid, nitric oxide, reactive oxygen species, prostaglandins and arachidonic acid, leading to the formation of an inflammatory microenvironment [139, 140]. Changes in the biological functions of various immune cells in microenvironment and the production of inflammatory mediators result in tumor cell escaping from immune surveillance.

Dendritic cells (DCs) are the most powerful professional antigen presenting cells in the body. Mature DCs can effectively activate the initial T cells and maintain the central part of the immune response [141, 142]. Tumor-derived and endogenous exosomal miRNAs can regulate cross-presentation in dendritic cells and with other immune cells, this exomsomal miRNAs-mediated intercellular communication may affect the maturation of DCs [143, 144]. In pancreatic cancer, exosomal miR-212-3p targets MHC class II TF RFXAP resulting in reduced expression of HLA-DR, -DP, and -DQ molecules and thus interfering with the function of DCs cells [145, 146]. Exosomal miR-203 is able to reduce the expression of TLR4, TNF-α and IL-12 in DCs, affecting the activation of natural killer cells (NKs) [147]. Up-regulated exosomal miR-let-7i in tumor-derived exosomes (TEX) can be taken up by mDCs, resulting in changes in intracellular levels of IL-6, IL-17, IL-1b, TGFbeta, SOCS1, KLRK1, IFNγ, and TLR4, thereby suppressing the immune response [148]. miRNAs from regulatory T cells (Treg) can also affect the immune response, EVs-mediated miR-150-5p and miR-142-3p can be transferred to DCs to induce a cell-refractory phenotype, resulting in increased IL-10 and decreased IL-6 expression [149], exosomal miR-let-7d is transferred to T helper 1 (Th1) cells to inhibit Th1 cells proliferation and IFNγ secretion, and IFNγ secreted by Th1 cells (a subtype of Naïve CD4 T cells) plays a central role in anti-tumor immunity [150].

Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in TME. TAMs play a huge role in the proliferation and migration of tumor cells and counteract the cytotoxic effect of T lymphocytes and NKs, facilitating cancer cells to evade immune surveillance [140, 151]. TAMs have strong plasticity and can differentiate into immune-stimulating (M1-polarized) TAMs or oppositely immune-suppressive (M2-polarized) TAMs, respectively, having different biological functions [152]. TAMs in tumors often behave as M2 phenotype and are usually associated with poor prognosis [153]. A large number of studies have reported that exosomal miRNAs can regulate the phenotypes of TAMs. Exosomal miR-125b derivied from lung adenocarcinoma cells promotes macrophage repolarization toward an anti-tumor M1 phenotype [154]. Exsomal miR-125b-5p secreted by melanoma cells targets LIPA and increases the expression of M1 phenotype markers IL-1β, CCL1, CCL2, and CD80 [71]. Oppositely, exosomal miR-21 taken up by CD14+ human monocytes inhibits the expression of the M1 marker and increases the expression of the M2 marker. Knockout of miR-21 in Snail-expressing human head and neck cancer cells attenuated M2 polarization of TAMs, and miR-21 was found to be positively correlated with M2 marker MRC1 in head and neck cancer tissues [155]. In epithelial ovarian cancer (EOC), exosomal miR-222-3p can be transferred to macrophages, down-regulating SOCS3, inducing phosphorylation of STAT3, and thus leading to polarization of the M2 macrophages [156]. In hypoxia, EOC-derived exosomal miR-21-3p, miR-125b-5p, miR-181d-5p, and miR-940 differentiate TAMs into M2 phenotypes and promote tumor progression [157, 158]. Likewise, exosomal miR-301a-3p derived from hypoxic pancreatic cancer cells activates the PTEN/PI3Kγ signaling pathway to trigger M2 phenotype polarization of macrophages [159, 160]. Mutant p53 colon cancer cells-derievd exosomal miR-1246 induces M2 polarization of macrophages and reshapes the TME through increase the expression of IL-10, TGFβ, and MMPs [161] (Fig.3).

Fig. 3.

The mechanism of immune microenvironment reshaping by exosomal miRNAs. Exosomes secreted by the primary tumor cells are taken up by the receptor immune cells, wherein the exosomal miR-212-3p target the MHC class II TF RFXAP complexus and activate the HLA-DR, -DP, and -DQ molecules. The exosomal miRNAs (miR-222-3p, miR-21, miR-10a, etc.) target the proteins (SOCS3, PTEN, RORA, etc.) and activate the molecules (p-STAT3, p-p65, p-AKT, p53, etc.). These exosomal miRNAs reshape inmune microenvironment by mediating immunosuppression.

Abnormal differentiation and function of myeloid cells is a hallmark of cancer. Among them, myeloid-derived suppressor cells (MDSCs) have the function of suppressing adaptive immunity and innate immune response, and play an important role in tumor immune escape [162,163,164]. Exosomal miRNAs affect the function of MDSCs by regulating the activity of transcription factors and transcription activators, thereby reshaping the immune microenvironment. In the research of glioblastoma, exosomal miR-10a targets RORA and affects the differentiation of MDSCs through the NFκB pathway, exosomal miR-21 targets PTEN and affects the activation of MDSCs via the p-STAT3/p-p65/p-Akt pathway [165]. Exosomal miR-155 istransmitted to monocytes, leading to nuclear translocation of NFkB and phosphorylation of STAT1, reprograming conventional monocytes into MDSCs [166]. Changes in the function of MDSCs affect the progression of the tumor itself. Recent research shows that exosmal miR-126a derived from MDSCs promotes angiogenesis and benefit breast cancer lung metastases [167].

The immunomodulation induced by exosomal miRNAs is complex and dynamic. In TME, tumor cells interact with various types of immune cells and cross-promote immunosuppressive activity. Among them, exosomal miRNAs play a pivotal role in them, but the mechanism has not been elucidated. Thereby, the function of exosomal miRNAs in the reciprocal interplays between cancer cells and hosts immune system merits further investigation.

Perspectives of exosomal miRNAs

With the vigorous development of the biology of exosomes in tumors, more and more evidence indicates that exosomal miRNAs play an important role in tumor progression and TME reshaping. Compared with miRNAs released directly into the circulatory system, exosomal miRNAs are protected by lipid bilayer encapsulation and avoid degradation by ribonuclease in the blood. Notebalely, exosomal miRNAs are more bioactive pool of circulating miRNAs compared to those miRNAs transported with liposomes [41, 168, 169]. Considering the advantages of exosomal miRNAs and the widespread presence of exosomes in all biological fluids (blood, breast milk, semen, and urine), diagnostic and therapeutic technologies based on exosomal miRNAs have a bright future.

Some specific exosomal miRNAs have high diagnostic value in tumors, and detecting them is helpful for early diagnosis of tumors. For example, in prostate cancer, breast cancer, and oral squamous cell carcinoma, the expression of exosomal miR-1246 is closely related to pathological grades, distant metastasis and poor prognosis [170,171,172,173]. Circulating exosomal miR-375 is valuable for the diagnosis of ovarian, rectal and prostate cancer [174,175,176]. The combination of multiple exosomal ncRNAs can enhance the diagnostic and prognostic potential of exosomal miRNAs. For example, the combination of expression of plasma exosomal miR-30d-5p and let-7d-3p is valuable diagnostic markers for non-invasive screening of cervical cancer and its precursors [177]. Circulating exosomal miRNA-21 and lncRNA-ATB are related to the TNM stage of liver cancer and other prognostic factors, including the T stage and portal vein thrombosis [178].

Exosomal miRNAs, as a new tumor treatment method, are being widely explored. Based on the fact that exosomal miRNAs effectively bind to target mRNA and inhibit gene expression in recipient cells, related exosomal engineering techniques have been used to treat tumors by delivering tumor suppressor exosomal miRNAs. For example, delivery of exogenous miR-155 into DCs using TEX as a vector results in increased expression of MHCII (I/A-I/E), CD86, CD40 and CD83, promoting activation of DCs. Exosomal miRNA-155 significantly increases the levels of IL12p70, IFN-γ and IL10 and improves immune function [179]. By fusing Her2 affinity to the extracellular N-terminus of human Lamp2, and then using the modified exosomes to co-deliver 5-FU and miR-21 inhibitors (miR-21i), which targets colon cancer cells, effectively reverses the resistance of tumor cells and significantly enhances the toxicity of 5-FU resistant cancer cells [180].

Although exosomal miRNAs have made exciting progress in oncology, most of these results are experimental. Extension of exosomal miRNAs technologies to clinic remains challenging. There is no doubt that the function of exosomes is determined by their specific contents. A large amount of literature has reported that tumor-derived exosomal miRNAs can reshape TME and promote tumor progression, but little is known about the sorting mechanism of exosomal miRNAs. Although the basic framework of the endosome sorting complex required for transport (ESCRT) and Ago2 in MVB sorting has been reported in previous studies, it remains to be elucidate whether other novel sorting signals are involved in the release of exosomal miRNAs [86, 181,182,183,184].

The potential of exosomal miRNAs as diagnostic markers is unquestionable, but how to improve the sensitivity and specificity of exosomal miRNAs remains to be solved. The combination of different exosomal cargos, such as proteins, lipids, RNA and miRNAs for cancer diagnosis and prognosis can more comprehensively reflect the characteristics of tumors. At the same time, the scope of application of exosomal miRNAs also needs attention. The expression level of exosomal miRNAs is related to tumor types, clinical stages or other underlying diseases, and there are differences between individual patients. Therefore, how to use exosomal miRNAs accurately is also worth of considering.

The widespread use of exosomal miRNAs in clinical treatment remains challenging. First, exosomes-based therapeutic tools require more accurate and standardized exosomal purification methods, and the economic cost of mass-producing exsomes for clinical application cannot be ignored [56, 57]. The second is that exosomal miRNAs-induced biological behavioral changes are often released through the cultivation of supra-physiological numbers of cell, and how many orders of magnitude of exosomal miRNAs are needed to achieve the corresponding efficacy in clinical applications remains to be determined.


Exosomal miRNAs, as a signaling molecule for communication between tumor cells and TME, play an important role in the formation and remodeling of TME, but its regulatory mechanism is still worth of further exploration. At present, most of the biological studies of exosomal miRNAs have been revealed by cell-culture systems in vitro. But the problems still remain whether exosomal miRNAs derived from supra-physiological numbers of cell reflect the biological conditions in vivo. It is necessary to conduct more experiments in vivo or in mammals.

With the increase of exosomes researches, people have gradually discovered that the exosomes obtained by traditional exosomal separation and purification methods (ultracentrifugation, density-gradient centrifugation, immune-affinity capture, and precipitation) not only contain sEVs, but also contain non-membrane structure vesicles (NVs). Components, double-stranded DNA (dsDNA) and histones, are more in the NVs rather than in exosomes or sEVs. Moreover, many of the most abundant miRNAs were more associated with extracellular NV fractions than with either parental cells or sEV fractions [56]. This indicates that we may need to re-evaluate the composition of exosomes, and it is urgent to explore the generation and sorting mechanisms of exosomal miRNAs or miRNAs in other type of sEVs.

Availability of data and materials

Not applicable.



Tumor microenvironment


Cancer-associated fibroblasts;


Extracellular matrix


Matrix metalloproteinases


Hypoxia inducible factor-1α


Vascular endothelial growth factor




Normal fibroblasts


Extracellular vesicles


Small extracellular vesicle


Intraluminal vesicles


Multivesicular bodies


Neural Sphingomyelinase 2


Heterogeneous nuclear Ribonucleoprotein


Argonaute 2


α-Smooth muscle actin


Fibroblast growth factor 2


Fibroblast activating protein


Sphingosine kinase 1


Colorectal cancer




Nasopharyngeal carcinoma


Human umbilical vein endothelial cells


Mesenchymal stem cells

PHD1 and PHD2:

Prolyl hydroxylase 1 and 2


Human liver stem-like cells


Dendritic cells


Natural killer cells


Regulatory T cells


Tumor-associated macrophages


Epithelial ovarian cancer


Myeloid-derived suppressor cells


Endosome sorting complex required for transport


Non-membrane structure vesicles


Double-stranded DNA


Gastric cancer


Non-small cell lung cancer


Chronic lymphocytic leukemia.


  1. 1.

    Li K, Chen Y, Li A, Tan C, Liu X. Exosomes play roles in sequential processes of tumor metastasis. Int J Cancer. 2019;144(7):1486–95.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Giraldo NA, Sanchez-Salas R, Peske JD, Vano Y, Becht E, Petitprez F, et al. The clinical role of the TME in solid cancer. Br J Cancer. 2019;120(1):45–53.

    PubMed  Article  Google Scholar 

  3. 3.

    Rossi GR, Trindade ES, Souza-Fonseca-Guimaraes F. Tumor Microenvironment-Associated Extracellular Matrix Components Regulate NK Cell Function. Front Immunol. 2020;11:73.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Zeltz C, Primac I, Erusappan P, Alam J, Noel A, Gullberg D. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins. Semin Cancer Biol. 2020;62:166-81.

  5. 5.

    Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–22.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Ma L, Hernandez MO, Zhao Y, Mehta M, Tran B, Kelly M, et al. Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer. Cancer Cell. 2019;36(4):418–30 e6.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Zhang X, Shen L, Liu Q, Hou L, Huang L. Inhibiting PI3 kinase-gamma in both myeloid and plasma cells remodels the suppressive tumor microenvironment in desmoplastic tumors. J Control Release. 2019;309:173–80.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Clement-Colmou K, Potiron V, Pietri M, Guillonneau M, Jouglar E, Chiavassa S, et al. Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models. Cancers (Basel). 2020;12:1.

    Article  Google Scholar 

  9. 9.

    Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I. The hypoxic tumour microenvironment. Oncogenesis. 2018;7(1):10.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Armignacco R, Cantini G, Poli G, Guasti D, Nesi G, Romagnoli P, et al. The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model. Cancers (Basel). 2019;11:12.

    Article  Google Scholar 

  11. 11.

    Lei X, Lei Y, Li JK, Du WX, Li RG, Yang J, et al. Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy. Cancer Lett. 2020;470:126–33.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19(1):43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17(8):457–74.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Moriwaki K, Asahi M. Augmented TME O-GlcNAcylation Promotes Tumor Proliferation through the Inhibition of p38 MAPK. Mol Cancer Res. 2017;15(9):1287–98.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Anfossi S, Fu X, Nagvekar R, Calin GA. MicroRNAs, Regulatory Messengers Inside and Outside Cancer Cells. Adv Exp Med Biol. 2018;1056:87–108.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Fattore L, Ruggiero CF, Pisanu ME, Liguoro D, Cerri A, Costantini S, et al. Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma. Cell Death Differ. 2019;26(7):1267-82.

  17. 17.

    Malhotra A, Sharma U, Puhan S, Chandra Bandari N, Kharb A, Arifa PP, et al. Stabilization of miRNAs in esophageal cancer contributes to radioresistance and limits efficacy of therapy. Biochimie. 2019;156:148–57.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Yan W, Wu X, Zhou W, Fong MY, Cao M, Liu J, 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(5):597–609.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Zhou CF, Ma J, Huang L, Yi HY, Zhang YM, Wu XG, et al. Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1. Oncogene. 2019;38(8):1256–68.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Cai L, Ye Y, Jiang Q, Chen Y, Lyu X, Li J, et al. Epstein-Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma. Nat Commun. 2015;6:7353.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Tian R, Wang J, Yan H, Wu J, Xu Q, Zhan X, et al. Differential expression of miR16 in glioblastoma and glioblastoma stem cells: their correlation with proliferation, differentiation, metastasis and prognosis. Oncogene. 2017;36(42):5861–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Xiao X, Lu Z, Lin V, May A, Shaw DH, Wang Z, et al. MicroRNA miR-24-3p Reduces Apoptosis and Regulates Keap1-Nrf2 Pathway in Mouse Cardiomyocytes Responding to Ischemia/Reperfusion Injury. Oxid Med Cell Longev. 2018;2018:7042105.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Song J, Ma Q, Hu M, Qian D, Wang B, He N. The Inhibition of miR-144-3p on Cell Proliferation and Metastasis by Targeting TOP2A in HCMV-Positive Glioblastoma Cells. Molecules. 2018;23:12.

    Google Scholar 

  24. 24.

    Sun J, Hong J, Sun S, Wang X, Peng Y, Zhou J, et al. Transcription factor 7-like 2 controls matrix degradation through nuclear factor kappaB signaling and is repressed by microRNA-155 in nucleus pulposus cells. Biomed Pharmacother. 2018;108:646–55.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Uddin MN, Li M, Wang X. Identification of Transcriptional Markers and microRNA-mRNA Regulatory Networks in Colon Cancer by Integrative Analysis of mRNA and microRNA Expression Profiles in Colon Tumor Stroma. Cells. 2019;8:9.

    Article  CAS  Google Scholar 

  26. 26.

    Slack FJ, Chinnaiyan AM. The Role of Non-coding RNAs in Oncology. Cell. 2019;179(5):1033–55.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Kanchan RK, Siddiqui JA, Mahapatra S, Batra SK, Nasser MW. microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy. Mol Cancer. 2020;19(1):29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Conti I, Varano G, Simioni C, Laface I, Milani D, Rimondi E, et al. miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment. Cells. 2020;9:1.

    Article  Google Scholar 

  29. 29.

    Tang X, Hou Y, Yang G, Wang X, Tang S, Du YE, et al. Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling. Cell Death Differ. 2016;23(1):132–45.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Baroni S, Romero-Cordoba S, Plantamura I, Dugo M, D'Ippolito E, Cataldo A, et al. Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts. Cell Death Dis. 2016;7(7):e2312.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Hunter S, Nault B, Ugwuagbo KC, Maiti S, Majumder M. Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer. Cancers (Basel). 2019;11:7.

    Article  CAS  Google Scholar 

  32. 32.

    Liu Y, Li X, Zhang Y, Wang H, Rong X, Peng J, et al. An miR-340-5p-macrophage feedback loop modulates the progression and tumor microenvironment of glioblastoma multiforme. Oncogene. 2019;38(49):7399–415.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Chen EB, Zhou ZJ, Xiao K, Zhu GQ, Yang Y, Wang B, et al. The miR-561-5p/CX3CL1 Signaling Axis Regulates Pulmonary Metastasis in Hepatocellular Carcinoma Involving CX3CR1(+) Natural Killer Cells Infiltration. Theranostics. 2019;9(16):4779–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Wu F, Li F, Lin X, Xu F, Cui R. Zhong J, et al. Endocr Relat Cancer: Exosomes increased angiogenesis in papillary thyroid cancer microenvironment; 2019.

    Google Scholar 

  35. 35.

    Hwang WL, Lan HY, Cheng WC, Huang SC, Yang MH. Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer. J Hematol Oncol. 2019;12(1):10.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:6478.

    Article  CAS  Google Scholar 

  37. 37.

    Tian X, Shen H, Li Z, Wang T, Wang S. Tumor-derived exosomes, myeloid-derived suppressor cells, and tumor microenvironment. J Hematol Oncol. 2019;12(1):84.

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin Immunol. 2018;35:69–79.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Cheng WC, Liao TT, Lin CC, Yuan LE, Lan HY, Lin HH, et al. RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer. Int J Cancer. 2019.

  40. 40.

    Patel H, Nilendu P, Jahagirdar D, Pal JK, Sharma NK. Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics. Cancer Biol Ther. 2018;19(1):3–12.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Wang M, Yu F, Ding H, Wang Y, Li P, Wang K. Emerging Function and Clinical Values of Exosomal MicroRNAs in Cancer. Mol Ther Nucleic Acids. 2019;16:791–804.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer. 2018;17(1):147.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Pontecorvi G, Bellenghi M, Puglisi R, Care A, Mattia G. Tumor-derived extracellular vesicles and microRNAs: Functional roles, diagnostic, prognostic and therapeutic options. Cytokine Growth Factor Rev. 2020;51:75–83.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Lucero R, Zappulli V, Sammarco A, Murillo OD, Cheah PS, Srinivasan S, et al. Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells. Cell Rep. 2020;30(7):2065–74 e4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Varricchi G, Loffredo S, Galdiero MR, Marone G, Cristinziano L, Granata F, et al. Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol. 2018;53:152–60.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Xie F, Zhou X, Fang M, Li H, Su P, Tu Y, et al. Extracellular Vesicles in Cancer Immune Microenvironment and Cancer Immunotherapy. Adv Sci (Weinh). 2019;6(24):1901779.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

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

  48. 48.

    Jarosz-Biej M, Smolarczyk R, Cichon T, Kulach N. Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy. Int J Mol Sci. 2019;20:13.

    Article  CAS  Google Scholar 

  49. 49.

    Peng J, Yang Q, Shi K, Xiao Y, Wei X, Qian Z. Intratumoral fate of functional nanoparticles in response to microenvironment factor: Implications on cancer diagnosis and therapy. Adv Drug Deliv Rev. 2019;143:37–67.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Gao X, Zhang Z, Mashimo T, Shen B, Nyagilo J, Wang H, et al. Gliomas Interact with Non-glioma Brain Cells via Extracellular Vesicles. Cell Rep. 2020;30(8):2489–500 e5.

    PubMed  Article  Google Scholar 

  51. 51.

    van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Yekula A, Yekula A, Muralidharan K, Kang K, Carter BS, Balaj L. Extracellular Vesicles in Glioblastoma Tumor Microenvironment. Front Immunol. 2019;10:3137.

    PubMed  Article  Google Scholar 

  53. 53.

    Xie M, Xiong W, She Z, Wen Z, Abdirahman AS, Wan W, et al. Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells. Front Immunol. 2020;11:13.

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Harmati M, Gyukity-Sebestyen E, Dobra G, Janovak L, Dekany I, Saydam O, et al. Small extracellular vesicles convey the stress-induced adaptive responses of melanoma cells. Sci Rep. 2019;9(1):15329.

  55. 55.

    Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, 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  PubMed Central  Article  Google Scholar 

  56. 56.

    Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of Exosome Composition. Cell. 2019;177(2):428–45 e18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Tian Y, Gong M, Hu Y, Liu H, Zhang W, Zhang M, et al. Quality and efficiency assessment of six extracellular vesicle isolation methods by nano-flow cytometry. J Extracell Vesicles. 2020;9(1):1697028.

    PubMed  Article  Google Scholar 

  58. 58.

    Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4):1208–15.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21(1):9–17.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Bebelman MP, Smit MJ, Pegtel DM, Baglio SR. Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther. 2018;188:1–11.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Rajagopal C, Harikumar KB. The Origin and Functions of Exosomes in Cancer. Front Oncol. 2018;8:66.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Kowal J, Tkach M, Thery C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–25.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Hyenne V, Labouesse M, Goetz JG. The Small GTPase Ral orchestrates MVB biogenesis and exosome secretion. Small GTPases. 2018;9(6):445–51.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Mills JT, Schwenzer A, Marsh EK, Edwards MR, Sabroe I, Midwood KS, et al. Airway Epithelial Cells Generate Pro-inflammatory Tenascin-C and Small Extracellular Vesicles in Response to TLR3 Stimuli and Rhinovirus Infection. Front Immunol. 2019;10:1987.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Gao K, Jin J, Huang C, Li J, Luo H, Li L, et al. Exosomes Derived From Septic Mouse Serum Modulate Immune Responses via Exosome-Associated Cytokines. Front Immunol. 2019;10:1560.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Castano C, Kalko S, Novials A, Parrizas M. Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc Natl Acad Sci U S A. 2018;115(48):12158–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Zhang Y, Hu YW, Zheng L, Wang Q. Characteristics and Roles of Exosomes in Cardiovascular Disease. DNA Cell Biol. 2017;36(3):202–11.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Gao G, Li C, Zhu J, Wang Y, Huang Y, Zhao S, et al. Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and Pro-Inflammatory Exosome Release. Front Immunol. 2020;11:161.

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Lai N, Wu D, Liang T, Pan P, Yuan G, Li X, et al. Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice. J Neuroinflammation. 2020;17(1):74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Ge X, Guo M, Hu T, Li W, Huang S, Yin Z, et al. Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI. Mol Ther. 2020;28(2):503–22.

    PubMed  Article  Google Scholar 

  71. 71.

    Gerloff D, Lutzkendorf J, Moritz RKC, Wersig T, Mader K, Muller LP, et al. Melanoma-Derived Exosomal miR-125b-5p Educates Tumor Associated Macrophages (TAMs) by Targeting Lysosomal Acid Lipase A (LIPA). Cancers (Basel). 2020;12:2.

    Article  Google Scholar 

  72. 72.

    Xiao Y, Zhong J, Zhong B, Huang J, Jiang L, Jiang Y, et al. Exosomes as potential sources of biomarkers in colorectal cancer. Cancer Lett. 2020;476:13–22.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Castellanos-Rizaldos E, Grimm DG, Tadigotla V, Hurley J, Healy J, Neal PL, 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.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Li ZG, Scott MJ, Brzoska T, Sundd P, Li YH, Billiar TR, et al. Lung epithelial cell-derived IL-25 negatively regulates LPS-induced exosome release from macrophages. Mil Med Res. 2018;5(1):24.

    PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Zhang Z, Xing T, Chen Y, Xiao J. Exosome-mediated miR-200b promotes colorectal cancer proliferation upon TGF-beta1 exposure. Biomed Pharmacother. 2018;106:1135–43.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Wu CX, Liu ZF. Proteomic Profiling of Sweat Exosome Suggests its Involvement in Skin Immunity. J Invest Dermatol. 2018;138(1):89–97.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Zhang P, Zhou H, Lu K, Lu Y, Wang Y, Feng T. Exosome-mediated delivery of MALAT1 induces cell proliferation in breast cancer. Onco Targets Ther. 2018;11:291–9.

    PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Guay C, Regazzi R. Exosomes as new players in metabolic organ cross-talk. Diabetes Obes Metab. 2017;19(Suppl 1):137–46.

    PubMed  Article  Google Scholar 

  79. 79.

    Schwarzenbach H, Gahan PB. MicroRNA Shuttle from Cell-To-Cell by Exosomes and Its Impact in Cancer. Noncoding RNA. 2019;5:1.

    Google Scholar 

  80. 80.

    Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem. 2013;288(15):10849–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Santangelo L, Giurato G, Cicchini C, Montaldo C, Mancone C, Tarallo R, et al. The RNA-Binding Protein SYNCRIP Is a Component of the Hepatocyte Exosomal Machinery Controlling MicroRNA Sorting. Cell Rep. 2016;17(3):799–808.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MAJ, Sadek P, Sie D, et al. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 2014;8(6):1649–58.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Yokoi A, Villar-Prados A, Oliphint PA, Zhang J, Song X, De Hoff P, et al. Mechanisms of nuclear content loading to exosomes. Sci Adv. 2019;5(11):eaax8849.

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Guduric-Fuchs J, O'Connor A, Camp B, O'Neill CL, Medina RJ, Simpson DA. Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics. 2012;13:357.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    McKenzie AJ, Hoshino D, Hong NH, Cha DJ, Franklin JL, Coffey RJ, et al. KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes. Cell Rep. 2016;15(5):978–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Xu R, Rai A, Chen M, Suwakulsiri W, Greening DW, Simpson RJ. Extracellular vesicles in cancer - implications for future improvements in cancer care. Nat Rev Clin Oncol. 2018;15(10):617–38.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Fabbri M. MicroRNAs and miRceptors: a new mechanism of action for intercellular communication. Philos Trans R Soc Lond B Biol Sci. 2018;373:1737.

    Article  CAS  Google Scholar 

  89. 89.

    Li I, Nabet BY. Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Mol Cancer. 2019;18(1):32.

    PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Wu P, Zhang B, Shi H, Qian H, Xu W. MSC-exosome: A novel cell-free therapy for cutaneous regeneration. Cytotherapy. 2018;20(3):291–301.

    PubMed  Article  Google Scholar 

  91. 91.

    Zhan C, Yang X. Yin X, Hou J. Oral Dis: Exosomes and other extracellular vesicles in oral and salivary gland cancers; 2019.

    Google Scholar 

  92. 92.

    Salarian M, Ibhagui OY, Yang JJ. Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol; 2020. p. e1622.

    Google Scholar 

  93. 93.

    Abyaneh HS, Regenold M, McKee TD, Allen C, Gauthier MA. Towards extracellular matrix normalization for improved treatment of solid tumors. Theranostics. 2020;10(4):1960–80.

    PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Sun Y, Wang R, Qiao M, Xu Y, Guan W, Wang L. Cancer associated fibroblasts tailored tumor microenvironment of therapy resistance in gastrointestinal cancers. J Cell Physiol. 2018;233(9):6359–69.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Houthuijzen JM, Jonkers J. Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. Cancer Metastasis Rev. 2018;37(4):577–97.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Alkasalias T, Moyano-Galceran L, Arsenian-Henriksson M, Lehti K. Fibroblasts in the Tumor Microenvironment: Shield or Spear? Int J Mol Sci. 2018;19:5.

    Article  CAS  Google Scholar 

  97. 97.

    Karakasheva TA, Lin EW, Tang Q, Qiao E, Waldron TJ, Soni M, et al. IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. Cancer Res. 2018;78(17):4957–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70(23):9621–30.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Wu HJ, Hao M, Yeo SK, Guan JL. FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication. Oncogene. 2020.

  100. 100.

    Yang X, Li Y, Zou L, Zhu Z. Role of Exosomes in Crosstalk Between Cancer-Associated Fibroblasts and Cancer Cells. Front Oncol. 2019;9:356.

    PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Zhang Y, Cai H, Chen S, Sun D, Zhang D, He Y. Exosomal transfer of miR-124 inhibits normal fibroblasts to cancer-associated fibroblasts transition by targeting sphingosine kinase 1 in ovarian cancer. J Cell Biochem. 2019.

  102. 102.

    Lu Y, Zhang T, Shan S, Wang S, Bian W, Ren T, et al. MiR-124 regulates transforming growth factor-beta1 induced differentiation of lung resident mesenchymal stem cells to myofibroblast by repressing Wnt/beta-catenin signaling. Dev Biol. 2019;449(2):115–21.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Frassanito MA, Desantis V, Di Marzo L, Craparotta I, Beltrame L, Marchini S, et al. Bone marrow fibroblasts overexpress miR-27b and miR-214 in step with multiple myeloma progression, dependent on tumour cell-derived exosomes. J Pathol. 2019;247(2):241–53.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Lv X, Li J, Hu Y, Wang S, Yang C, Li C, et al. Overexpression of miR-27b-3p Targeting Wnt3a Regulates the Signaling Pathway of Wnt/beta-Catenin and Attenuates Atrial Fibrosis in Rats with Atrial Fibrillation. Oxid Med Cell Longev. 2019;2019:5703764.

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Wang J, Guan X, Zhang Y, Ge S, Zhang L, Li H, et al. Exosomal miR-27a Derived from Gastric Cancer Cells Regulates the Transformation of Fibroblasts into Cancer-Associated Fibroblasts. Cell Physiol Biochem. 2018;49(3):869–83.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Dai G, Yao X, Zhang Y, Gu J, Geng Y, Xue F, et al. Colorectal cancer cell-derived exosomes containing miR-10b regulate fibroblast cells via the PI3K/Akt pathway. Bull Cancer. 2018;105(4):336–49.

    PubMed  Article  Google Scholar 

  107. 107.

    Liang HX, Sun LB, Liu NJ. Neferine inhibits proliferation, migration and invasion of U251 glioma cells by down-regulation of miR-10b. Biomed Pharmacother. 2019;109:1032–40.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Yoshii S, Hayashi Y, Iijima H, Inoue T, Kimura K, Sakatani A, et al. Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression. Cancer Sci. 2019;110(8):2396–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Zhou X, Yan T, Huang C, Xu Z, Wang L, Jiang E, et al. Melanoma cell-secreted exosomal miR-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway. J Exp Clin Cancer Res. 2018;37(1):242.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Hu J, Huang CX, Rao PP, Cao GQ, Zhang Y, Zhou JP, et al. MicroRNA-155 inhibition attenuates endoplasmic reticulum stress-induced cardiomyocyte apoptosis following myocardial infarction via reducing macrophage inflammation. Eur J Pharmacol. 2019;857:172449.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Jiang C, Guo Y, Yu H, Lu S, Meng L. Pleiotropic microRNA-21 in pulmonary remodeling: novel insights for molecular mechanism and present advancements. Allergy Asthma Clin Immunol. 2019;15:33.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Fang T, Lv H, Lv G, Li T, Wang C, Han Q, 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Lawson J, Dickman C, Towle R, Jabalee J, Javer A, Garnis C. Extracellular vesicle secretion of miR-142-3p from lung adenocarcinoma cells induces tumor promoting changes in the stroma through cell-cell communication. Mol Carcinog. 2019;58(3):376–87.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Qin X, Guo H, Wang X, Zhu X, Yan M, Wang X, et al. Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5. Genome Biol. 2019;20(1):12.

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Ham IH, Lee D, Hur H. Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments. J Oncol. 2019;2019:6270784.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Deepak KGK, Vempati R, Nagaraju GP, Dasari VR, N S, Rao DN, et al. Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 2020;153:104683.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Hashimoto K, Ochi H, Sunamura S, Kosaka N, Mabuchi Y, Fukuda T, et al. Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A. Proc Natl Acad Sci U S A. 2018;115(9):2204–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Wang FT, Sun W, Zhang JT, Fan YZ. Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer. Oncol Lett. 2019;17(3):3055–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25(4):501–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Bao L, You B, Shi S, Shan Y, Zhang Q, Yue H, et al. Metastasis-associated miR-23a from nasopharyngeal carcinoma-derived exosomes mediates angiogenesis by repressing a novel target gene TSGA10. Oncogene. 2018;37(21):2873–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Lu S, Xu Q. MicroRNA-23a inhibits melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the MAPK/ERK signaling pathway. IUBMB Life. 2019;71(5):587–600.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Sun X, Ma X, Wang J, Zhao Y, Wang Y, Bihl JC, et al. Glioma stem cells-derived exosomes promote the angiogenic ability of endothelial cells through miR-21/VEGF signal. Oncotarget. 2017;8(22):36137–48.

    PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Sabry D, El-Deek SEM, Maher M, El-Baz MAH, El-Bader HM, Amer E, et al. Role of miRNA-210, miRNA-21 and miRNA-126 as diagnostic biomarkers in colorectal carcinoma: impact of HIF-1alpha-VEGF signaling pathway. Mol Cell Biochem. 2019;454(1-2):177–89.

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Lin XJ, Fang JH, Yang XJ, Zhang C, Yuan Y, Zheng L, et al. Hepatocellular Carcinoma Cell-Secreted Exosomal MicroRNA-210 Promotes Angiogenesis In Vitro and In Vivo. Mol Ther Nucleic Acids. 2018;11:243–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Masoumi-Dehghi S, Babashah S, Sadeghizadeh M. microRNA-141-3p-containing small extracellular vesicles derived from epithelial ovarian cancer cells promote endothelial cell angiogenesis through activating the JAK/STAT3 and NF-kappaB signaling pathways. J Cell Commun Signal. 2020.

  127. 127.

    Pakravan K, Babashah S, Sadeghizadeh M, Mowla SJ, Mossahebi-Mohammadi M, Ataei F, et al. MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1alpha/VEGF signaling axis in breast cancer cells. Cell Oncol (Dordr). 2017;40(5):457–70.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Kim DH, Park S, Kim H, Choi YJ, Kim SY, Sung KJ, et al. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4. Cancer Lett. 2020;475:2–13.

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    He L, Zhu W, Chen Q, Yuan Y, Wang Y, Wang J, et al. Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis. Theranostics. 2019;9(26):8206–20.

    PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Farrugia MK, Vanderbilt DB, Salkeni MA, Ruppert JM. Kruppel-like Pluripotency Factors as Modulators of Cancer Cell Therapeutic Responses. Cancer Res. 2016;76(7):1677–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, 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.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Chen X, Yang F, Zhang T, Wang W, Xi W, Li Y, et al. MiR-9 promotes tumorigenesis and angiogenesis and is activated by MYC and OCT4 in human glioma. J Exp Clin Cancer Res. 2019;38(1):99.

    PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Zhao S, Li J, Zhang G, Wang Q, Wu C, Zhang Q, et al. Exosomal miR-451a Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Targeting LPIN1. Cell Physiol Biochem. 2019;53(1):19–35.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Lu J, Liu QH, Wang F, Tan JJ, Deng YQ, Peng XH, et al. Exosomal miR-9 inhibits angiogenesis by targeting MDK and regulating PDK/AKT pathway in nasopharyngeal carcinoma. J Exp Clin Cancer Res. 2018;37(1):147.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    Lopatina T, Grange C, Fonsato V, Tapparo M, Brossa A, Fallo S, et al. Extracellular vesicles from human liver stem cells inhibit tumor angiogenesis. Int J Cancer. 2019;144(2):322–33.

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Vignard V, Labbe M, Marec N, Andre-Gregoire G, Jouand N, Fonteneau JF, et al. MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma. Cancer Immunol Res. 2020;8(2):255–67.

    PubMed  Article  Google Scholar 

  138. 138.

    Schmittgen TD. Exosomal miRNA Cargo as Mediator of Immune Escape Mechanisms in Neuroblastoma. Cancer Res. 2019;79(7):1293–4.

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Netea-Maier RT, Smit JWA, Netea MG. Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship. Cancer Lett. 2018;413:102–9.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    van Dalen FJ, van Stevendaal M, Fennemann FL, Verdoes M, Ilina O. Molecular Repolarisation of Tumour-Associated Macrophages. Molecules. 2018;24:1.

    Article  CAS  Google Scholar 

  141. 141.

    Fotaki G, Jin C, Ramachandran M, Kerzeli IK, Karlsson-Parra A, Yu D, et al. Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses. Oncoimmunology. 2018;7(3):e1395126.

    PubMed  Article  Google Scholar 

  142. 142.

    Diao J, Gu H, Tang M, Zhao J, Cattral MS. Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses. J Immunol. 2018;201(4):1306–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Kikete S, Chu X, Wang L, Bian Y. Endogenous and tumour-derived microRNAs regulate cross-presentation in dendritic cells and consequently cytotoxic T cell function. Cytotechnology. 2016;68(6):2223–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012;119(3):756–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Ding G, Zhou L, Shen T, Cao L. IFN-gamma induces the upregulation of RFXAP via inhibition of miR-212-3p in pancreatic cancer cells: A novel mechanism for IFN-gamma response. Oncol Lett. 2018;15(3):3760–5.

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget. 2015;6(30):29877–88.

    PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L. Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol. 2014;292(1-2):65–9.

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Taghikhani A, Hassan ZM, Ebrahimi M, Moazzeni SM. microRNA modified tumor-derived exosomes as novel tools for maturation of dendritic cells. J Cell Physiol. 2019;234(6):9417–27.

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Tung SL, Boardman DA, Sen M, Letizia M, Peng Q, Cianci N, et al. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Sci Rep. 2018;8(1):6065.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. 150.

    Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, et al. MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells. Immunity. 2014;41(3):503.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Grossman JG, Nywening TM, Belt BA, Panni RZ, Krasnick BA, DeNardo DG, et al. Recruitment of CCR2(+) tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer. Oncoimmunology. 2018;7(9):e1470729.

    PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Eichmuller SB, Osen W, Mandelboim O, Seliger B. Immune Modulatory microRNAs Involved in Tumor Attack and Tumor Immune Escape. J Natl Cancer Inst. 2017;109:10.

    Article  CAS  Google Scholar 

  153. 153.

    Choo YW, Kang M, Kim HY, Han J, Kang S, Lee JR, et al. M1 Macrophage-Derived Nanovesicles Potentiate the Anticancer Efficacy of Immune Checkpoint Inhibitors. ACS Nano. 2018;12(9):8977–93.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Trivedi M, Talekar M, Shah P, Ouyang Q, Amiji M. Modification of tumor cell exosome content by transfection with wt-p53 and microRNA-125b expressing plasmid DNA and its effect on macrophage polarization. Oncogenesis. 2016;5(8):e250.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Hsieh CH, Tai SK, Yang MH. Snail-overexpressing Cancer Cells Promote M2-Like Polarization of Tumor-Associated Macrophages by Delivering MiR-21-Abundant Exosomes. Neoplasia. 2018;20(8):775–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Ying X, Wu Q, Wu X, Zhu Q, Wang X, Jiang L, et al. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget. 2016;7(28):43076–87.

    PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Chen X, Zhou J, Li X, Wang X, Lin Y, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype. Cancer Lett. 2018;435:80–91.

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Chen X, Ying X, Wang X, Wu X, Zhu Q, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep. 2017;38(1):522–8.

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, et al. Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kgamma to Promote Pancreatic Cancer Metastasis. Cancer Res. 2018;78(16):4586–98.

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, et al. Correction: Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kgamma to Promote Pancreatic Cancer Metastasis. Cancer Res. 2020;80(4):922.

    PubMed  Article  Google Scholar 

  161. 161.

    Cooks T, Pateras IS, Jenkins LM, Patel KM, Robles AI, Morris J, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun. 2018;9(1):771.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. 162.

    DeVito NC, Plebanek MP, Theivanthiran B, Hanks BA. Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion. Front Immunol. 2019;10:2876.

    PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Mohammadpour H, MacDonald CR, Qiao G, Chen M, Dong B, Hylander BL, et al. beta2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J Clin Invest. 2019;129(12):5537–52.

    PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Yang Z, Guo J, Weng L, Tang W, Jin S, Ma W. Myeloid-derived suppressor cells-new and exciting players in lung cancer. J Hematol Oncol. 2020;13(1):10.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Guo X, Qiu W, Liu Q, Qian M, Wang S, Zhang Z, et al. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways. Oncogene. 2018;37(31):4239–59.

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Bruns H, Bottcher M, Qorraj M, Fabri M, Jitschin S, Dindorf J, et al. CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D. Leukemia. 2017;31(4):985–8.

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J, et al. Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene. 2017;36(5):639–51.

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Cheng L, Sharples RA, Scicluna BJ, Hill AF. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles. 2014;3.

  169. 169.

    Zickler AM, El Andaloussi S. Functional extracellular vesicles aplenty. Nat Biomed Eng. 2020;4(1):9–11.

    PubMed  Article  Google Scholar 

  170. 170.

    Bhagirath D, Yang TL, Bucay N, Sekhon K, Majid S, Shahryari V, et al. microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer. Cancer Res. 2018;78(7):1833–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Li XJ, Ren ZJ, Tang JH, Yu Q. Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer. Cell Physiol Biochem. 2017;44(5):1741–8.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Sakha S, Muramatsu T, Ueda K, Inazawa J. Exosomal microRNA miR-1246 induces cell motility and invasion through the regulation of DENND2D in oral squamous cell carcinoma. Sci Rep. 2016;6:38750.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Zhai LY, Li MX, Pan WL, Chen Y, Li MM, Pang JX, et al. In Situ Detection of Plasma Exosomal MicroRNA-1246 for Breast Cancer Diagnostics by a Au Nanoflare Probe. ACS Appl Mater Interfaces. 2018;10(46):39478–86.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Meltzer S, Bjornetro T, Lyckander LG, Flatmark K, Dueland S, Samiappan R, et al. Circulating Exosomal miR-141-3p and miR-375 in Metastatic Progression of Rectal Cancer. Transl Oncol. 2019;12(8):1038–44.

    PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Su YY, Sun L, Guo ZR, Li JC, Bai TT, Cai XX, et al. Upregulated expression of serum exosomal miR-375 and miR-1307 enhance the diagnostic power of CA125 for ovarian cancer. J Ovarian Res. 2019;12(1):6.

    PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Foj L, Ferrer F, Serra M, Arevalo A, Gavagnach M, Gimenez N, et al. Exosomal and Non-Exosomal Urinary miRNAs in Prostate Cancer Detection and Prognosis. Prostate. 2017;77(6):573–83.

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Zheng M, Hou L, Ma Y, Zhou L, Wang F, Cheng B, et al. Exosomal let-7d-3p and miR-30d-5p as diagnostic biomarkers for non-invasive screening of cervical cancer and its precursors. Mol Cancer. 2019;18(1):76.

    PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Lee YR, Kim G, Tak WY, Jang SY, Kweon YO, Park JG, et al. Circulating exosomal noncoding RNAs as prognostic biomarkers in human hepatocellular carcinoma. Int J Cancer. 2019;144(6):1444–52.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Asadirad A, Hashemi SM, Baghaei K, Ghanbarian H, Mortaz E, Zali MR, et al. Phenotypical and functional evaluation of dendritic cells after exosomal delivery of miRNA-155. Life Sci. 2019;219:152–62.

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Liang G, Zhu Y, Ali DJ, Tian T, Xu H, Si K, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    McAndrews KM, Kalluri R. Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer. 2019;18(1):52.

    PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Jiang W, Ma P, Deng L, Liu Z, Wang X, Liu X, et al. Hepatitis A virus structural protein pX interacts with ALIX and promotes the secretion of virions and foreign proteins through exosome-like vesicles. J Extracell Vesicles. 2020;9(1):1716513.

    PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Villarroya-Beltri C, Baixauli F, Mittelbrunn M, Fernandez-Delgado I, Torralba D, Moreno-Gonzalo O, et al. ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat Commun. 2016;7:13588.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Leidal AM, Huang HH, Marsh T, Solvik T, Zhang D, Ye J, et al. The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles. Nat Cell Biol. 2020;22(2):187–99.

    CAS  PubMed  Article  Google Scholar 

Download references


Not applicable.


This work was supported in part by grants from the following sources: the National Natural Science Foundation of China (81972636, 81872281), the Natural Science Foundation of Hunan Province (2019JJ40175, 2019JJ40183, 2018JJ1013, 2017JJ3190), the Research Project of the Health and Family Planning Commission of Hunan Province (B20180400, B20180582), and the Changsha Science and Technology Board (kq1706045, kq1706043), Ascend Foundation of National cancer center (NCC2018b68).

Author information




Shiming Tan and Longzheng Xia contributed to drafting and editing of the manuscript, shared the first authorship. Qianjin Liao and Yujuan Zhou designed, revised and finalized the manuscript. Pin Yi, Qing Pan, Lu Tang, Yaqian Han, Jiaxin Liang, Linda Oyang, and Deliang Cao participated in the drafting and editing manuscript. Yutong Tian, Shan Rao participated in the revision and coordination. Pin Yi, Jinguan Lin, Shiming Tan contributed to literature search. Min Su, Yingrui Shi participated in the conception and coordination. All authors contributed toward data analysis, drafting and revising the paper and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yujuan Zhou or Qianjin Liao.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tan, S., Xia, L., Yi, P. et al. Exosomal miRNAs in tumor microenvironment. J Exp Clin Cancer Res 39, 67 (2020).

Download citation


  • exosomal miRNAs
  • tumor microenvironment (TME)
  • CAFs
  • angiogenesis
  • immune microenvironment