The Role and Mechanisms of Tumor-Derived Exosomes in the Formation of the Premetastatic Niche

Abstract

The premetastatic niche is a specialized microenvironment established by tumor cells prior to the formation of metastatic foci in distant organs. This niche provides an optimal landing site for circulating tumor cells. As key mediators of intercellular communication, exosomes play a pivotal role in shaping the premetastatic niche. This review analyzes the effects of exosomes on premetastatic niche formation from multiple perspectives, including angiogenesis, metabolic reprogramming, matrix remodeling, immune response, organicity, and epithelial-mesenchymal transition (EMT). Their value in tumor diagnosis, prognosis, and treatment, as well as the challenges and opportunities for future clinical transformation are discussed. This article presents a narrative review conducted in accordance with the SANRA guidelines.

Keywords

exosomes premetastatic niche tumor metastasis

Introduction

The metastatic spread of malignant tumors is the primary cause of patient mortality and is a key indicator of poor prognosis. To better understand and combat this process, Lyden initially proposed the concept of the premetastatic niche.¹ The premetastatic niche refers to a microenvironment shaped by the primary tumor prior to the formation of metastatic foci, providing a favorable “soil’’ for metastatic colonization. The progression from the establishment of the premetastatic niche to the completion of metastasis is a multistage process. It involves the primary tumor releasing various cytokines and signaling factors to remotely regulate the tumor niche, followed by microenvironmental remodeling to accommodate circulating tumor cells and ultimately the infiltration of tumor cells into specific target organs to accomplish metastasis.² Key components in this process include tumor-derived exosomes, bone marrow-derived dendritic cells (BMDCs), host stromal cells and secreted cytokines.³ For example, Costa-Silva et al reported that exosomal macrophage migration inhibitory factor (MIF), derived from pancreatic ductal adenocarcinomas, can be taken up by mouse Kupffer cells and alter their secretory phenotype, thus promoting liver metastasis through the recruitment of BMDCs.⁴

Although initial research suggested that exosomes are byproducts of cellular metabolism, numerous subsequent studies have demonstrated their ability to convey biological information and mediate intercellular communication.⁵ Exosomes are naturally occurring bioactive vesicles, typically 30–100 nm in diameter, enclosed by a lipid bilayer. This lipid bilayer protects their contents—such as proteins, lipids, and RNA—from degradation by biological enzymes.⁶ The synthesis of exosomes begins in the endocytic pathway and progresses through the formation of early endosomes, late endosomes, and multivesicular bodies (MVBs) containing luminal vesicles. MVBs are ultimately transported to the plasma membrane and fuse with it, resulting in the release of their intraluminal vesicles as exosomes into the extracellular space.⁵ Exosomes regulate intercellular communication in two main ways. First, the protein molecules on the surface of exosomes act as ligands, binding to target cell membrane receptors to activate signaling pathways. Second, exosomes can directly fuse with target cell membranes, allowing their own proteins, nucleic acids, and other substances to be transferred into recipient cells, thereby regulating cellular behavior and function^7,8 (Figure 1). An increasing number of studies have demonstrated that tumor-derived exosomes can act as carriers to deliver their bioactive cargo to specific distant organs prior to metastasis. This process facilitates the establishment of a suitable premetastatic niche, which promotes the dissemination of circulating tumor cells (Figure 2). In this narrative review, we summarize these findings following the SANRA guidelines.⁹

Figure 1.

Tumor derived exosome content and mechanisms underlying the establishment of the premetastatic niche

Figure 2.

Mechanisms of exosome biogenesis and cellular uptake

Exosomes Facilitate the Formation of the Premetastatic Niche by Enhancing Angiogenesis and Vascular Permeability

Tumor-derived exosomes promote angiogenesis and increase vascular permeability in recipient cells within the premetastatic niche, thereby creating favorable conditions for the dissemination of tumor cells. These exosomes exhibit enhanced vasotropic activity under hypoxic conditions.^10,11 For instance, human antigen R (HuR) is a powerful bioenhancer of epithelial barrier function, and circ-ZNF609, derived from exosomes secreted by hypoxic esophageal squamous cell carcinoma cells, can suppress the expression of vascular endothelial junctional adhesion molecules by interacting with HUR, thereby disrupting the vascular barrier and creating a suitable premetastatic microenvironment for distant tumor colonization.¹² On the basis of these findings, it is important to address whether the formation of the premetastatic niche primarily depends on the early proangiogenic activity of exosomes or it is further reinforced by hypoxia-enhanced angiogenesis at later stages of tumor progression. In addition, Jin, Jie et al demonstrated that non-small cell lung cancer (NSCLC)-derived exosomal miR-374a-5p directly targets γ-adducin (ADD3) to regulate the distribution of tight junction proteins in brain microvascular endothelial cells and enhance blood-brain barrier permeability, which in turn promotes meningeal metastasis.¹³

In addition to directly affecting the vascular barrier, Qiu Shengkui et al reported that exosomal miR-519a-3p enhances liver metastasis of gastric cancer by inducing M2 polarization in intrahepatic macrophages and upregulating vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor D (VEGFD) expression, which is a key step in establishing the premetastatic niche in the liver.¹⁴ Similarly, glioblastoma-derived exosomal miR-374b-3p has been shown to promote angiogenesis by modulating macrophage polarization.¹⁵

Furthermore, lncRNAs such as MFI2 antisense RNA 1 (MFI2-AS1) have been demonstrated to competitively bind to miR-107, thereby activating the AKT signaling pathway, promoting angiogenesis and inducing the formation of a premetastatic niche in NSCLC.¹⁶ Recently, Wang Jifei’s team reported that exosomal miR-182-5p derived from cholangiocarcinoma cells activates the PI3K/AKT/mTOR signaling pathway, thereby promoting vascular endothelial cell proliferation and angiogenesis by modulating ADK expression and SEMA5A methylation.¹⁷

Proteins carried by exosomes can play similar roles in promoting metastasis. Exosomes released from lung metastases contain LAP-TGF-β1, a protein dimer composed of latency-associated peptide (LAP) and the TGF-β1 active subunit, which is capable of impairing zonula occludens-1 (ZO-1) expression in lung endothelial cells and remodeling the pulmonary vascular niche.¹⁸ Moreover, exosomes can mediate angiogenesis through receptor–ligand interactions metalloproteinase17 (ADAM17), which is present in exosomes derived from colorectal cancer cells and has been shown to disrupt junctions between vascular endothelial cells and induce vascular leakage. This process is thought to contribute to the formation of a premetastatic microenvironment through the selective targeting of VE-cadherin. However, the precise site of action of this protein remains to be elucidated.¹⁹

These studies indicate that exosomes participate in angiogenesis and enhance vascular permeability, thereby promoting the formation of a premetastatic niche. They not only disrupt the vascular endothelial barrier but also stimulate angiogenesis by regulating endothelial cell proliferation and macrophage polarization and activating signaling pathways such as the PI3K/AKT/mTOR pathway. Additionally, proteins carried by exosomes, including LAP-TGF-β1 and ADAM17, regulate vascular endothelial connections and reshape the vascular microenvironment. These mechanisms collectively create favorable conditions for circulating tumor cells to colonize distant organs, underscoring the critical role of exosomes in the formation of the premetastatic microenvironment.

Exosomes Facilitate the Formation of the Premetastatic Niche Through Metabolic Reprogramming

Recent studies have shown that tumor-derived exosomes play a role in shaping the premetastatic niche through the induction of metabolic changes in recipient cells, notably emphasizing glycolytic reprogramming. Increased glycolysis leads to lactate accumulation, not only mirroring tumor-related metabolic alterations but also serving as a crucial metabolic signaling factor in restructuring the microenvironment. Lactate, by modulating EMT, angiogenesis, and immune responses, facilitates the development of a premetastatic niche conducive to tumor spread and distant settlement.^20,21 Liang et al reported that circSIPA1L3 can be transported via exosomes to neighboring breast cancer cells, promoting glycolysis and increasing lactate production. The conditioned medium from circSIPA1L3-overexpressing cells increased lactate levels, which enhanced the migration and tumor-promoting functions of tumor-associated macrophages (TAMs). However, the study did not determine whether lactate itself is directly delivered to TAMs via exosomes. Therefore, we hypothesize that exosome-mediated lactate transfer can locally influence macrophage metabolism and promote M2-like polarization. Alternatively, lactate may affect TAMs through nonexosome-dependent mechanisms, such as passive diffusion. Future studies are needed to clarify the relative contributions of these pathways.²² On the other hand, exosomes derived from cancer-associated fibroblasts (CAFs) carrying lncRNAs, such as NNT-AS1, have also been shown to remodel glucose metabolism in pancreatic ductal adenocarcinoma (PDAC).²³ Wu Xia et al reported that in nasopharyngeal carcinoma, latent membrane protein 1 (LMP1) packaged in exosomes can activate fibroblasts to transform into CAFs. This process is mediated by the NF-κB p65 pathway, shifting the metabolic phenotype of these cells from oxidative phosphorylation to aerobic glycolysis. Activated CAFs further provide lactate and β-hydroxysobutyrate (β-HB) as energy substrates, supporting aerobic metabolism in tumor cells and promoting the formation of the nasopharyngeal carcinoma premetastatic niche.²⁴ Additionally, Xu et al reported that dormant cancer cells can transfer insulin-like growth factor 2 (IGF-2) to bone marrow stromal cells (BMSCs) via exosomes, activating the insulin-like growth factor 1 receptor (IGF-1R) signaling pathway, enhancing glycolysis, and promoting lactate secretion. The formation of a premetastatic niche in the bone marrow supports the survival of lung cancer cells, which may be one of the reasons for the likelihood of lung cancer relapse after chemotherapy.²⁵

Additionally, exosomes have been shown to facilitate the establishment of the premetastatic niche through lipid metabolic reprogramming. ROLLCSC, transferred via exosomes from lung cancer stem cells, increases lipid metabolism and the metastatic potential of low-metastatic, nonstem lung cancer cells through the miR-5623-3p and miR-217-5p pathways.²⁶ Furthermore, exosomal HSPC111 released by colorectal cancer cells affects lipid metabolism in CAFs, thereby contributing to the formation of a premetastatic niche in the liver. Elevated levels of acetyl coenzyme A in CAFs are essential for CXCL5 production, which in turn promotes the release of additional exosomal HSPC111 from colorectal cancer cells via the CXCL5/CXCR2 pathway, creating a positive regulatory feedback loop.²⁷ Huang Jiaying and colleagues reported that gastric cancer–derived exosomal CD44 triggers the reprogramming of fatty acid oxidative metabolism in BMSCs by regulating the ERK/PPARγ/CPT1A signaling pathway, thereby establishing a favorable microenvironment for the lymphatic metastasis of gastric cancer.²⁸

Glutamine metabolic reprogramming is a common metabolic change in tumors. Glutamine enters the cytoplasm via specific transporters and is converted to glutamate. Liu et al reported that the CAF-derived exosomal lncRNA LINC01614 activates NF-κB by targeting ANXA2 and p65, which increases the expression of the glutamine transporters SLC38A2 and SLC7A5, increases glutamine uptake by cancer cells, and promotes tumor progression under nutrient-deprived conditions.²⁹ In addition, CAF-derived exosomes can redirect carbon flux from oxidative glucose metabolism to glutamine metabolism via reductive carboxylation in the TCA cycle, increasing intracellular glutamine levels and driving metabolic reprogramming.³⁰ However, current research focuses mainly on glycolysis and lipid metabolism. The mechanism by which exosomes affect the amino acid metabolism of cancer cells should be explored as an emerging research direction.

Exosomes Facilitate the Formation of a Premetastatic Niche Through the Remodeling of the Extracellular Matrix

During tumor metastasis, exosomes contribute to the remodeling of stromal cells within the premetastatic niche through diverse molecular mechanisms. These interactions promote the differentiation of stromal cells into protumorigenic phenotypes, thereby creating a microenvironment conducive to subsequent tumor cell colonization and outgrowth. Among these processes, the activation and phenotypic reprogramming of CAFs appear to play a central role.³¹ He Tao et al reported that circ-EHD2 is selectively packaged into exosomes derived from renal cell carcinoma cells in a hnRNPA2B1-dependent manner. Upon uptake by stromal cells, these exosomes promote the activation of CAFs and stimulate interleukin-6 (IL-6) secretion, thereby enhancing the metastatic potential of renal cell carcinoma cells.³² In ovarian cancer, exosomal miR-141 directly suppresses the expression of YAP1, a downstream effector of the Hippo signaling pathway. This suppression leads to elevated production of the proinflammatory chemokine GROα, which in turn promotes the conversion of resident fibroblasts into proinflammatory CAFs and contributes to the establishment of a prometastatic inflammatory microenvironment.³³ Liu Guoqing’s group reported that the exosomal protein piR-25783 derived from ovarian cancer cells facilitates the transition of omental fibroblasts into myofibroblasts. This process is mediated through activation of the TGF-β/SMAD2/SMAD3 signaling pathway and is implicated in the formation of a premetastatic niche within the omentum.³⁴

M2 macrophage polarization has also been implicated in extracellular matrix remodeling during metastasis. In the context of breast cancer metastasis, Wang and colleagues reported that exosomal Cav-1 interacts with lung fibroblasts to upregulate tenascin-C expression, resulting in increased matrix deposition and structural remodeling of the pulmonary niche. This process involves a complex signaling network, including the modulation of niche-associated gene expression and inflammatory chemokine profiles in lung epithelial cells. Additionally, it inhibits the PTEN/CCL2/VEGF-A signaling pathway in lung macrophages to facilitate their M2-type polarization and angiogenesis.³⁵

Exosomes Facilitate the Formation of a Premetastatic Niche Through Immunosuppression and Immunosurveillance

Tumor-derived exosomes modulate the recruitment and function of immune cells, thereby creating a permissive environment for tumor cell invasion, distant organ colonization, and immune surveillance evasion. Exosomes derived from colorectal cancer cells carrying TGF-β1 promote the transdifferentiation of hepatic stellate cells (HSCs) into cells with a CAF-like phenotype.³⁶ This phenotypic shift facilitates the recruitment of myeloid-derived suppressor cells (MDSCs) to the hepatic premetastatic niche, which are a heterogeneous population of immature myeloid cells with immunosuppressive effects that undergo massive expansion during tumor progression.³⁷ Deng et al reported that the exosomal protein TGF-β1 released by osteosarcoma cells activates the JAK2/STAT3 signaling pathway in pulmonary mesenchymal macrophages. This activation induces CXCL2 secretion, which in turn leads to the recruitment of granulocytic myeloid-derived suppressor cells (gMDSCs) to the lungs, thereby facilitating the formation of a supportive premetastatic niche in osteosarcoma lung metastasis.³⁸ In pancreatic cancer, tumor-derived exosomes have similarly been implicated in the recruitment of MDSCs through multiple signaling pathways, further supporting the formation of a premetastatic niche characterized by immune evasion and stromal remodeling.³⁹ Jia Xuebing’s group reported that IPG1576, an inhibitor of macrophage migration inhibitory factor isomerase activity, can effectively counteract tumor metastasis through blocking exosome-induced differentiation and recruitment of MDSCs. The administration of IPG1576 not only reduces the number of MDSCs in the tumor microenvironment but also enhances CD8⁺ T cell infiltration, thereby attenuating the formation of an immunosuppressive niche.⁴⁰ In addition to MDSCs, the polarization of immune cells such as neutrophils and macrophages plays a critical role in facilitating tumor invasion and colonization. In breast cancer, exosomes have been shown to mediate Lin28B-driven lung metastasis by recruiting neutrophils to the pulmonary premetastatic niche and inducing their polarization toward the N2 phenotype, accompanied by upregulation of programmed death-ligand 2 (PD-L2) expression.⁴¹ In 2004, Brinkmann et al demonstrated that activated neutrophils can release neutrophil extracellular traps (NETs) into the extracellular space. These structures entrap platelets on the surface of circulating tumor cells, forming a physical barrier that shields them from immune surveillance and supports immune evasion. It is plausible that exosome-induced N2 polarization may enhance NET formation, further promoting the development of the premetastatic niche. In head and neck squamous cell carcinoma (HNSCC), exosomal ABHD12 induces tumor-promoting macrophage phenotypes through activation of the AKT–FoxO1 signaling axis.⁴² Notably, Yang Depeng and colleagues reported that targeting the PI3K/Akt or NF-κB signaling pathway can inhibit M2 polarization while promoting M1 differentiation. This reprogramming of the macrophage phenotype suppresses tumor growth and has emerged as a promising therapeutic strategy in cancer immunotherapy.⁴³

Exosomes can also directly inhibit immune system function and induce immune tolerance. Melanoma exosomes can transfer tumor antigens to lymphatic endothelial cells, remodeling draining lymph nodes, and ultimately leading to the apoptosis of CD8⁺ T cells, thus preventing adaptive immune responses.⁴⁴ Moreover, they can inhibit the activity of the natural killer group 2 member D (NKG2D) receptor by expressing NKG2D ligands, thereby inhibiting the normal function of NK cells and disrupting their capacity for cell killing.⁴⁵ Tumor cells are also capable of evading immune responses by releasing immunosuppressive factors in collaboration with regulatory T cells. Therefore, we can conclude that the exosome-induced increase in the number of CD4+FoxP3+ Tregs is highly important for the formation of an immune-tolerant premetastatic niche.⁴⁶

Recent studies have shown that exosomes derived from colorectal cancer can regulate the tumor immune microenvironment through the STING signaling pathway. The nuclear chromatin and mitochondrial DNA fragments carried by exosomes can be taken up by macrophages, leading to activation of the STING pathway, phosphorylation of STAT1, and increased secretion of IL-6. The accumulated IL-6 released by macrophages, in turn, induced colorectal cancer cell EMT through the activation of IL6R/STAT3 signaling, indicating that DNA carried by exosomes could influence the behavior of immune cells and may support the formation of a premetastatic niche.⁴⁷

Emerging evidence from 2023 to 2025 has further clarified the multifaceted role of exosomes in tumor immunotherapy. For example, compared with conventional dendritic cell vaccines, dendritic cell-derived exosomes enriched with MHC class I/II molecules and costimulatory proteins have demonstrated superior immunogenicity and stability in murine models of melanoma, NSCLC and hepatocellular carcinoma.⁴⁸ Additionally, a recent study revealed that exosomal apolipoprotein E secreted by CAFs could bind to GRP78 in tumor cells and suppress its ATPase activity, which downregulated MHC-I surface expression, thereby weakening antigen presentation and impairing CD8⁺ T cell–mediated cytotoxicity. Notably, treatment with the GRP78 agonist EZ-482 could restore MHC-I expression and sensitize tumors to anti-programmed cell death protein 1 (anti–PD-1) therapy in preclinical models, suggesting a novel strategy to overcome fibroblast-derived exosome–mediated immune suppression.⁴⁹ Notably, exosomes are being increasingly leveraged as low-immunogenicity nanocarriers to codeliver immune checkpoint inhibitors and chemotherapeutic agents such as doxorubicin, providing the dual benefit of targeted delivery and immune modulation.⁵⁰ Moreover, diffuse large B-cell lymphoma-derived exosomal enolase 2 (ENO2) accelerated glycolysis via the GSK3β/β-catenin/c-Myc signaling pathway to ultimately promote macrophage differentiation to the M2-like phenotype, suggesting that exosomal ENO2 may be a promising therapeutic target and prognostic biomarker for diffuse large B-cell lymphoma.⁵¹ Collectively, these advances underscore the dual role of exosomes—as immunosuppressive mediators and engineered therapeutic platforms, which offer new opportunities for combination tumor immunotherapy.

Exosomes determine organotropism to promote premetastatic niche formation

The organotropism of exosomes refers to the ability to bind to target organ stromal cells via specific integrin proteins on their surfaces, thereby mediating organ-specific metastasis and facilitating the formation of a premetastatic niche. Accumulating evidence indicates that distinct integrin profiles on the exosomal surface constitute a central molecular determinant of exosomal organotropism. For instance, integrin αvβ5 preferentially binds to the fibronectin-enriched liver and promotes liver-specific metastasis, whereas integrins α6β4 and α6β1 exhibit high affinity for the lung, thereby facilitating the establishment of a premetastatic niche in the lung.⁵² Given that the liver is the most frequent site of metastasis in pancreatic cancer, these observations suggest that pancreatic cancer–derived exosomes may also exploit αvβ5-mediated mechanisms to achieve liver tropism. However, the precise molecular basis of this process remains to be experimentally validated.

Beyond integrin-mediated exosomal targeting, the bioactive cargo encapsulated within exosomes plays a pivotal role in orchestrating the formation of organ-specific premetastatic niches. Ruan, Xianhui et al reported that high levels of miR-199b-5p carried by exosomes derived from metastatic breast cancer promote brain-specific metastasis by targeting solute carrier transporter proteins in astrocytes and neurons.⁵³ In addition, Li, Xiaoqing et al demonstrated that the high expression of the transcription factor runt-related transcription factor 2 (RUNX2) in breast cancer cells could increase the acquisition of osteomimetic properties, which in turn release exosomes expressing calreticulin cadherin 11 (CDH11) and integrin α5 (ITGA5), which are responsible for the formation of the preosteogenic metastatic niche.⁵⁴

Furthermore, environmental factors have been shown to influence tumor-specific metastasis. Mu Wei et al revealed that exposure to benzo(a)pyrene enables hepatocellular carcinoma-derived exosomal circ_0011496 to competitively bind to lung fibroblast miR-486-5p and activate its tumor-promoting properties, which involve increased secretion of cytokines, including interleukin-11 (IL-11), matrix metalloproteinase 9 (MMP9), and VEGF, creating favorable conditions for lung metastasis in hepatocellular carcinoma.⁵⁵

The organotropism of exosomes also confers antitumor therapeutic potential. Nie, Huifang et al demonstrated that the combination of exosomal integrin β4 (ITGβ4) with surfactant-associated protein C (SPC) on the surface of lung epithelial cells can induce the pneumophilic properties of breast cancer. On the basis of these findings, exosomes were used as drug carriers to deliver miR-126 to inhibit the PTEN/PI3K/AKT signaling pathway and thereby attenuate lung metastasis in patients with breast cancer.⁵⁶

In conclusion, exosomes facilitate the formation of a premetastatic niche through the transport of specific molecules, including integrins, calmodulin, and microRNAs, which interact with organ-specific target cells to induce organotropism. These findings provide a significant theoretical foundation for the development of novel tumor therapeutic strategies.

Exosomes Promote Premetastatic Niche Formation by Inducing EMT

EMT is a critical step during tumor metastasis. It transforms noninvasive epithelial tumor cells into invasive mesenchymal-like cells. This process is essential for tumor cells to detach from the primary site, disseminate through the blood and lymphatic system, and form metastatic lesions in distant organs. Hu JL et al reported that CAFs can transfer exosomes to colorectal cancer cells, leading to a significant increase in the level of miR-92a-3p in colorectal cells and contributing to cell stemness and EMT.⁵⁷ Similarly, in pancreatic ductal adenocarcinoma, tumor-derived exosomes carrying lncRNA-Sox2ot promote EMT and confer stem-like properties on tumor cells by modulating Sox2 expression, thereby enhancing their metastatic adaptability.⁵⁸ In addition, Liu Yawei’s team reported that fibroblasts derived from colorectal cancer cells express exosomal TP53TG1, which directly targets miR-330-3p, thereby inducing epithelial mesenchymal transformation in colorectal cancer and promoting metastasis. Furthermore, the effects of TP53TG1 on colorectal cancer can be reversed by increased expression of miR-330-3p.⁵⁹

Notably, exosomes can also enhance tumor resistance to chemotherapeutic agents. Wang et al reported that the expression of HOTTIP was upregulated in cisplatin-resistant gastric cancer cells and that HOTTIP was transferred to sensitive cells via exosomes, facilitating the spread of cisplatin resistance. As a competitive endogenous RNA, HOTTIP binds to miR-218, alleviating its inhibitory effect on HMGA1. This interaction resulted in the upregulation of HMGA1 expression, which promoted cell proliferation, migration, invasion, and EMT in cisplatin-resistant gastric cells.⁶⁰ Moreover, Hu et al further demonstrated that CAF-derived exosomes secreted LINC00355, which induced EMT in colorectal cancer and conferred multidrug resistance to chemotherapeutic agents such as cisplatin, 5-FU, and oxaliplatin. This effect was achieved through the inhibition of miR-34b-5p, leading to increased expression of CRKL.⁶¹

In addition, the TGF-β signaling pathway is regarded as a principal inducer of EMT. Pucci, Marzia et al reported that colorectal cancer-derived exosomes can induce EMT in hepatocytes by triggering TGF-β signaling, which may contribute to hepatic fibrosis and shape a microenvironment conducive to metastasis. Nevertheless, the precise molecular mechanisms through which EMT promotes fibrosis remain to be further explored.⁶² C-Src, as a protooncogene, profoundly influences the invasive and proliferative characteristics of tumors. Shen, Yuzhou et al revealed that metastatic NSCLC cells can utilize exosomes to deliver c-Src to primary NSCLC cells, which in turn triggers the TGF-β signaling pathway to undergo EMT, thereby enhancing tumor metastasis. Therefore, c-Src is a crucial upstream regulator of the TGF-β signaling pathway.⁶³

These findings reveal the dual role of EMT in tumor metastasis and chemotherapy resistance and provide potential targets for the development of new therapeutic strategies. Inhibiting key signaling pathways involved in EMT, such as the TGF/Smad pathway, or by decreasing the expression levels of lncRNAs may help to overcome tumor aggressiveness and drug resistance.

Discussion

This comprehensive review provides an in-depth analysis of the multifaceted role of tumor-derived exosomes in the formation of the premetastatic niche. Exosomes, as critical mediators of intercellular communication, have been shown to significantly influence various biological processes that facilitate tumor metastasis. These processes include angiogenesis, metabolic reprogramming, immunosuppression, extracellular matrix remodeling, EMT and organotropism. This review highlights numerous studies demonstrating how exosomes modulate the recipient cell environment to create a favorable niche for tumor colonization and growth in distant organs. However, an increasing body of evidence suggests that key components of exosomes often cross-regulate multiple mechanisms simultaneously, creating synergistic effects that accelerate tumor progression and metastasis. For example, VEGF not only serves as an angiogenic factor to stimulate neovascularization but also modulates the immune microenvironment by suppressing CD8⁺ T cell activation and infiltration, thereby enhancing immune suppression. Glioblastoma exosomes carry VEGF, which is critical for angiogenesis.⁴⁵ Magali Terme et al reported that VEGF-A production in the tumor microenvironment could increase the expression of PD-1 and other inhibitory checkpoints involved in CD8⁺ T cell exhaustion, which could be reversed by treatment with anti-VEGF/VEGFR.⁶⁴ Moreover, as discussed in this review, TGF-β functions as a central node linking EMT, ECM remodeling, and immunosuppression. It directly activates the TGF-β/Smad signaling pathway to induce EMT in tumor cells, thereby increasing their invasive and metastatic potential. It also drives the transdifferentiation of omental fibroblasts into myofibroblasts and of HSCs into CAF-like phenotypes, contributing to ECM remodeling and the recruitment of immunosuppressive cells. In colorectal cancer, exosomal TGF-β induced EMT in hepatocytes, promoted hepatic fibrosis, and established an “EMT–fibrosis–immunosuppression” positive-feedback loop that shaped a liver-specific premetastatic niche favorable for metastatic colonization.

Notably, studies of exosome-mediated premetastatic niche formation suggest that there is a need to address whether hypoxia-driven angiogenesis is an early or late event. Hypoxia-inducible factors (HIFs) are widely expressed in human cancers. Pahlman et al reported that HIF2α is stable under moderate hypoxia (2–5% O₂), whereas HIF1α accumulates only under more severe hypoxia (0–2% O₂). HIF1α expression increases sharply during early hypoxic exposure but decreases after several hours, whereas HIF2α expression remains relatively high after 48 hours of sustained hypoxia. Moreover, sustained HIF2α expression promotes tumor angiogenesis and invasion by upregulating VEGF expression. Thus, we propose that during early tumor development, exosomes contribute to the nascent vascular network and facilitate adaptation to hypoxia via transient HIF1α accumulation. In the late stage, as hypoxia intensifies, HIF2α is activated, and exosomes further increase angiogenesis and permeability in the tumor microenvironment by carrying HIF2α and VEGF.⁶⁵

Additionally, the potential of exosomes as diagnostic and prognostic biomarkers for tumor progression and metastasis has become increasingly evident. For example, compared with those in healthy individuals, the levels of miRNA-17-5p and miRNA-21 expression in serum exosomes were found to be particularly high in patients with pancreatic cancer. Subsequent studies have also revealed that a combination of six miRNAs (let-7b-5p, miR-223-3p, miR-192-5p, miR-19a-3p, miR-19b-3p and miR-25-3p) can improve the sensitivity and specificity of the diagnosis of pancreatic cancer.⁶⁶ In patients with colorectal cancer, enrichment of specific proteins in plasma exosomes, including glycated fibrinogen β-chain and β-2-glycoprotein 1, may also serve as the basis for early diagnosis.⁶⁷ In patients with pancreatic cancer, the upregulation of portal vein exosomal miR-4525, miR-451a, and miR-21 is typically associated with higher recurrence rates and shorter survival. Compared with healthy individuals, patients with pancreatic cancer with poor quality of life have significantly different levels of exosomal circRNA-PDE8A and circRNA-IARS expression.⁶⁶

Furthermore, the potential therapeutic applications of exosomes in cancer treatment have garnered increasing interest. Studies have shown that compared with traditional intravenous paclitaxel injection, exosome-loaded paclitaxel not only improves drug delivery efficiency but also significantly reduces nontargeted toxicity.⁶⁸ In addition, exosomes can transfer CUB domain-containing protein 1 (CDCP1), which is overexpressed in lung cancer cells after exposure to 8 Gy irradiation, to dendritic cells, promoting the aggregation, infiltration and activation of CD4+ and CD8+ T cells; destroying tumors; and combining immunotherapy and radiotherapy.^69,70 Multidrug resistance in tumor cells is difficult to overcome in cancer treatment. Pgp-1/ABC-B1 expression significantly increases in hepatocytes expressing MDR, promoting drug resistance. Exosomes, as drug carriers, can bypass the PGP-1-mediated excretion system and deliver drugs to tumor cells.^71,72 Moreover, exosomes carrying miR-107 significantly increase the sensitivity of cisplatin-resistant gastric cancer cells by targeting the HMGA2/mTOR/P-gp pathway.⁷³ Phatsapong Yingchoncharoen et al developed an engineered exosome containing IL3-Lamp2B loaded with imatinib, which can deliver BCR-ABL siRNA to chronic myeloid leukemia cells, improve imatinib resistance and reduce tumor volume.⁷⁴

However, although the therapeutic potential of targeted exosome-based interventions has been increasingly acknowledged, there are still challenges and opportunities facing the clinical translation of exosome research. First, physiological barriers in the body can reduce the efficiency of exosome drug delivery. In lung cancer, the blood-gas barrier and blood-lung barrier impede the effective delivery of exosomes to the tumor site. Moreover, the small blood vessels in lung cancer tissue, obvious ventilation-perfusion mismatch, and excessive airflow in the airways can further hinder exosome penetration.⁷⁵ In the gastrointestinal tract, exosomes must be able to withstand the harsh environment of gastric acid and digestive enzymes and cross the intestinal barrier before reaching tumor targets, increasing their bioavailability in the intestine.⁷⁶ In addition, the blood-brain barrier has become a major obstacle to the treatment of neurological tumors with exosomes. Second, although exosomes have great potential for immunomodulation, they may also be phagocytosed by immunosuppressive cells or rejected by the PD-1/PD-L1 pathway, reducing their targeting efficiency.^77,78 Tumor-derived exosomes also contain various oncogenes, which makes the safety of tumor exosome-based vaccines uncertain.⁷¹ Finally, exosomes are inherently heterogeneous in size, origin, molecular cargo, and biological functions, posing significant challenges for standardization and interpretation.⁷⁹ To address this, multiple analytical techniques are currently employed to characterize exosomes, including nanoparticle tracking analysis, transmission electron microscopy, tunable resistive pulse sensing, western blotting of canonical markers (CD9, CD63, CD81, and TSG101), and high-resolution flow cytometry.^80,81 Moreover, the isolation and purification process of exosomes is complex, and the yield is low. It is also necessary to maintain their biological similarity to naturally secreted exosomes. Furthermore, the production process is usually complex and resource intensive, and cost reduction has become another major obstacle.⁸²

In conclusion, while this review provides valuable insights into the roles of tumor-derived exosomes in the formation of the premetastatic niche, several critical challenges remain to be addressed in future research. A deeper focus on elucidating molecular mechanisms, developing targeted therapeutic strategies, identifying reliable biomarkers, and expanding investigations into nontumor contexts will be essential to unlock the full potential of exosomes in both cancer treatment and broader medical applications.

Footnotes

ORCID iD

Jichao Wang

Ethical Considerations

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Author Contributions

All authors contributed to the study conception and design. Material preparation and the first draft of the manuscript was written by Jichao Wang and Jianxin Ye commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Appendix

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