Abstract

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammation of the gut characterized by an imbalance in the intestinal microbiome and ecology. IBD raises the risk of developing colorectal cancer (CRC). CRC is one of the most commonly diagnosed cancers in the world, with high incidence rates. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are vital for maintaining intestinal homeostasis. Recent research highlights novel inflammatory mediators, such as specialized pro-resolving mediators (SPMs), damage-associated molecular patterns (DAMPs), alarmins, non-coding RNAs (ncRNAs), and metabolic intermediates, as crucial in the pathophysiology of IBD and CRC. These novel inflammatory mediators are transported by EVs, influencing the pathogenesis of IBD and associated CRC. Therefore, this article examines the role of novel inflammatory mediators transported by EVs in the pathogenesis of IBD and related CRC, as well as the interaction between EVs and the tumor microenvironment. We also review new research on EV use as a diagnostic indicator and on the potential of EVs, such as mesenchymal stem cell-derived EVs (MSC-EVs), as therapeutic delivery channels for cancer treatment targeting unique inflammatory mediators.

1 Introduction

Inflammatory bowel disease (IBD) is a group of persistent, nonspecific inflammatory gut disorders caused by a combination of immunological, genetic, environmental, and other factors. IBD has two subtypes, including ulcerative colitis (UC) and Crohn’s disease (CD), which are characterized by debilitating and chronic recurring and resolving inflammation in the gut and gastrointestinal system, respectively (Ocansey et al., 2020). The incidence of IBD has increased dramatically in both industrialized and developing countries, and people are now being diagnosed at an increasing age (Agrawal and Jess, 2022). Compared with low-income regions, high-income countries have seen a decline in IBD-CRC incidence due to improved surveillance systems and advanced disease treatment strategies. However, underreporting in low- and middle-income areas masked the global burden (Kapadia et al., 2025). Although the cause and pathophysiology of IBD are complex and unknown, recent research has focused on the interplay between chronic intestinal inflammation and the intestinal milieu. In IBD patients, the increased production of extracellular vesicles (EVs) and changes in their contents play a dual role in the intestinal environment, serving both pro-inflammatory and anti-inflammatory functions by influencing macrophage polarization and aiding microbial rebuilding (Shen et al., 2022).

IBD is a persistent, recurring condition, and the cumulative effects of chronic inflammation on long-term IBD patients are connected with an increased risk of CRC, referred to as colitis-associated colorectal cancer (CAC) (Xia et al., 2023). Compared to sporadic CRC, IBD-driven tumors frequently manifest with a distinct mutation pattern, extremely heterogeneous hyperplasia, and worse survival rates (Choi et al., 2017). The major mechanism by which chronic inflammation drives IBD-associated CRC involves triggering inflammation and accelerating the repetitive cycles of epithelial injury and repair, which promotes mutagenesis (Porter et al., 2021). Therefore, understanding the mechanism of association between IBD and CRC is vital for prevention and treatment.

EVs are structures composed of proteins and phospholipids that cells continuously release. They can be found in both small particles measuring 30 to 200 nm and larger, micron-sized particles (Shen et al., 2022). The sources of EV are vast and varied, and almost all cell types can produce them (Figure 1). The well-studied origins of EVs are shown in Figure 1. As crucial participants in intercellular communication, they transport not only membrane proteins and lipids but also ribonucleic acid (RNA), cytoplasmic proteins, and other signaling chemicals to the recipient cell. Exosomes, microvesicles, and apoptotic bodies are the three primary groups of EVs based on their biogenesis (Shen et al., 2022). They are crucial for normal physiological functions such as blood coagulation, immunological surveillance, tissue repair, and stem cell maintenance, as well as for the pathology of various illnesses, including cancer and inflammation (S et al., 2013). Numerous studies have reported that dysbiosis of the gut microbiota in patients with IBD, along with the aberrant metabolism of intestinal epithelial cells (IECs), is associated with alterations in the quantity of EV cargo (Chang et al., 2020). Moreover, in individuals with gastrointestinal malignancy, exosome-loaded microRNAs (miRNAs) and proteins have markedly different expression patterns (Matsumura et al., 2015).

Different origins of widely studied EVs. Presently, in-depth research on EV primarily focuses on the human body, animals, and plants. EVs can carry a variety of substances, including intracellular proteins, lipids, DNA, RNA, membrane proteins, and other signaling molecules. PDEV, plant-derived extracellular vesicle; DNA, deoxyribonucleic acid; RNA, ribonucleic acid; circRNA, circular RNA; lncRNA, long non-coding RNA; miRNA, microRNA.

The pathogenesis of IBD and CRC has long focused on the role of classical cytokines and chemokines. However, novel inflammatory mediators have gone beyond these classical molecules and become emerging core participants in the pathogenesis of IBD and CRC. They regulate inflammation, tissue damage, and tumor development either positively or negatively through various mechanisms, including SPMs, alarmins, DAMPs, non-coding RNAs, and metabolic intermediates (Gobbetti et al., 2017; Santana et al., 2024). Therefore, research on novel inflammatory mediators is expected to overcome the limitations of traditional therapies and restore immune stability. Hence, this review examines the role of EVs from various origins in IBD and their progression to CRC, focusing on the transport and regulation of specific inflammatory molecules. It also provides a research direction and potential therapeutic target for IBD treatment in the future by further investigating the interaction of novel inflammatory mediators and EVs on the gut, exploring the therapeutic potential of targeting EVs and novel inflammatory mediators in IBD and CRC, and providing new strategies for precision intervention of IBD and IBD-associated CRC. Also, all forms of EVs, including exosomes, tiny extracellular vesicles, and small vesicles, will be included in the review, due to the paucity of research on novel inflammatory mediators in EVs.

2 Extracellular vesicles as key players in IBD pathogenesis2.1 EVs in the inflamed intestinal microenvironment

EVs in IBD mainly come from immunological cells (dendritic cells (DCs), macrophages, T cells, and B cells), IECs, endothelial cells, and fibroblasts (Shen et al., 2022). EVs are classified into three types based on their biogenesis: exosomes, tiny vesicles, and apoptotic bodies (Figure 2). EVs in the gastrointestinal system contain various molecular components depending on their progenitor cells, which determine EVs’ activity (Li et al., 2023). Therefore, measuring signature molecules can identify the source of EVs. In the physiological environment, IECs secrete EVs from the apical or basolateral surfaces, and these EVs contain immunomodulatory molecules expressed on their surface, such as major histocompatibility complex (MHC)-I, MHC-II, and human leukocyte antigen-DM (HLA-DM) (Mallegol et al., 2007). They mainly interact with DCs to improve antigen presentation and maintain intestinal homeostasis; under inflammatory conditions, their expression levels are significantly higher than those of basic molecules (Mallegol et al., 2007). EVs produced by IECs expressing integrin αβ6 can activate regulatory T (Treg) cells and promote immune tolerance (Chen et al., 2011). However, in the inflammatory environment, the intestinal microenvironment promotes cellular stress and tissue inflammation by altering the biogenesis and content of EVs (Tkach et al., 2017). EVs are a great way to transport particular chemicals to recipient cells. Hence, inflammatory mediators, the major players in IBD, are contained by EVs and gradually delivered to target cells in the gut mucosa, where they execute specialized functions. These functions include modulating immunological responses, maintaining the gut barrier integrity, and influencing the intestinal flora in IBD.

Classification of EVs is based on their biogenesis, release, and uptake. EVs comprise apoptotic bodies, microvesicles, and exosomes. Exosomes are produced by budding from multivesicular bodies. Microvesicles are generated intracellularly from the extracellular membrane. Apoptotic bodies form when cells fragment during cell death. EV uptake mechanisms include direct fusion of EV membranes with the plasma membrane, resulting in the discharge of contents into recipient cells, as well as endocytosis, phagocytosis, and macropinocytosis.

2.2 Regulation of inflammatory responses by EVs in IBD

In general, the anti-inflammatory or pro-inflammatory functions of EVs are determined by their different cellular origins and cargos (Li et al., 2023). For individual EV, there is no switch between anti-inflammatory and pro-inflammatory effects. In fact, a substantial number of EVs from various origins interact with target cells and the intestinal microenvironment, forming a complex network that ultimately manifests as pro-inflammatory or anti-inflammatory phenotypes (Shen et al., 2022). In conditions of barrier impairment or dysbiosis (Camilleri et al., 2012; Imai et al., 2019), the gut tends to have a pro-inflammatory phenotype. When the intestinal barrier is intact and the microbiome is healthy (Leoni et al., 2015; Jacobs et al., 2016), the gut tends to exhibit an anti-inflammatory phenotype.

2.2.1 EVs as pro-inflammatory signals

EVs regulate immune responses by transporting inflammatory mediators and other substances between immune cells. The proliferation of MHC I, MHC II, and HLA-DM, which occurs on the surface of EVs in an inflammatory state, can act as pro-inflammatory signals to activate a wider range of CD8+ and CD4+ T cells and release IFN-γ, leading to a more intense inflammatory response (Mallegol et al., 2007). In addition to surface markers, pro-inflammatory signals can also be released from within EVs. A study found that EVs released from the intestinal inflammation site in IBD patients exhibit a unique protein and mRNA profile compared with those from normal individuals (Ocansey et al., 2020). EVs from IBD patients with a high endoscopic score (≥1) contained significantly higher mRNA and protein levels of interleukin (IL)-6, IL-8, IL-17, and tumor necrosis factor (TNF)-α than EVs from healthy controls. Additionally, these EVs also showed pro-inflammatory effects on colon epithelial cells in vitro (Chen L. et al., 2023). Among the inflammatory cytokines, TNF-α promotes apoptosis and inflammation in IECs (Zhang C. et al., 2025); however, IFN-γ activates macrophages and neutrophils and boosts immune-cell recruitment by activating adhesion molecules on intraepithelial cells (Li et al., 2019). IL-17 promotes the release of IL-8 from epithelial cells, stimulating the recruitment of neutrophils and Th17 cells to inflamed tissues (Jiang et al., 2023). Nevertheless, the lack of IL-17 exacerbates DSS-induced colitis, suggesting that IL-17 also has a beneficial effect (Strober et al., 2002). In general, EVs act as pro-inflammatory signals by activating immunological cells through the transfer of inflammatory mediators, promoting cytokine production, and ultimately recruiting immune cells.

2.2.2 EVs as anti-inflammatory signals

As anti-inflammatory signals, EVs are usually derived from anti-inflammatory cells or contain regulatory molecules. For example, M2b macrophages release a variety of anti-inflammatory mediators, such as transforming growth factor (TGF)-β, IL-10, C-C motif ligand 1 (CCL1), CCL17, and others. These anti-inflammatory mediators inhibit the activation of immune cells, thereby promoting tissue repair and regeneration (Hu et al., 2021). As a result, using EVs to deliver modulating molecules to treat intestinal inflammation has emerged as a viable method. Therapy with exosomes containing IL-10 led to a significant elevation of IL-10 mRNA levels in intestinal tissues and in Tregs in the lamina propria, suppressing acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis (Yang et al., 2010). Under physiological conditions, IECs secrete TGF-β1-dependent EVs with immunosuppressive activity. These EVs can reduce the severity of dextran sulfate sodium (DSS)-induced IBD in mice by stimulating Tregs and immunosuppressive DCs (Jiang et al., 2016). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can also effectively alleviate gut inflammation by inhibiting mediators that promote inflammation (e.g., TNF-α, IL-6, IL-1β) and enhancing anti-inflammatory agents (e.g., IL-10, IL-4) (Clua-Ferré et al., 2024). However, extensive experimental and clinical research is required before MSC-EVs may be used as a successful treatment regimen for IBD and related CRC.

2.2.3 The context-dependent and cell-type-specific effects of EVs in IBD

It is worth mentioning that the function of EVs in IBD depends on specific environmental conditions and cell types. The predominant focus of current immunological research is on DCs, T cells, and macrophages.

T cells, particularly Th17 cells (pro-inflammatory) and Tregs (anti-inflammatory), play an important role in adaptive immunological reactions and are required for IBD pathogenesis. A loss of balance between Treg and Th17 cells is the primary cause of gut tolerance dysfunction, leading to the establishment and progression of IBD (Zhang S. et al., 2024). Restoring the normal Th17/Treg ratio helps restore the intestinal microenvironment. In a mouse colitis model, exosomes derived from olfactory ecto-MSCs reduced the immune response by suppressing Th17 and Th1 cell growth while increasing Treg cell production (Tian et al., 2020). Studies have found that mice with blocked IL-17 exhibited more severe disease and symptoms of DSS-induced colitis. Interestingly, mice lacking interleukin-17 receptor (IL-17R) or treated with an interleukin-17 receptor immunoglobulin (IL-17R-Ig) fusion protein showed reduced IBD progression following TNBS induction. The dual role of IL-17 in maintaining the intestinal barrier has been indicated earlier, suggesting that its expression may depend on specific environmental and local inflammatory states within the microenvironment (Jiang et al., 2023; Strober et al., 2002).

Macrophages are closely associated with EV and IBD, and macrophage infiltration is often observed in the inflamed sites of IBD patients, altering the numbers and proportions of CD4+ T cell populations. Macrophages differentiate into two types based on their environment: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages (Luo et al., 2024). In the pathogenesis of IBD, the imbalance between M1/M2 macrophages, driven by dysregulation of macrophage plasticity, is a critical factor. As key mediators of intercellular communication, EVs regulate macrophage polarization by delivering specific cargo. Intestinal macrophages in IBD patients exhibit a higher proportion of M1-like phenotypes, with surface markers of clusters of differentiation (CD)11c, CC chemokine receptor (CCR)2, HLA-DR, CD64, CD206, and CD209. They can produce inflammatory substances such as IL-23 and TNF-α, increase Th17, and contribute to microbial dysbiosis (Chang et al., 2020). Wei et al. demonstrated that adipocytes secrete pro-inflammatory EV-miR-155 into the blood circulation, which is then absorbed by macrophages in the intestine. These macrophages undergo M1-like polarization, thereby inducing chronic intestinal inflammation (Wei et al., 2020). Moreover, numerous studies indicate that promoting macrophage polarization toward an M2 phenotype is a promising therapeutic strategy for IBD. Compared with traditional IL-4, IL-10, and miRNAs that induce M2 polarization, EVs can be specifically recognized by receptor cells, thereby enabling more precise induction of macrophage M2 polarization. MSC-EV has been widely used, with successful transplantation in IBD animal models, providing a theoretical foundation for future clinical applications. By polarizing M2b macrophages in IBD colitis models, systemically delivered human bone marrow MSC-derived exosomes significantly reduce inflammation without inducing intestinal fibrosis. A study demonstrated that adipose tissue-derived mesenchymal stem/stromal cell (ASC)-derived EVs modulate the intestinal immune environment by reversing macrophage polarization, thereby effectively alleviating the severity of colitis. Tumor necrosis factor-α-stimulated gene/protein-6 (TSG-6) plays a key role in the polarization of macrophages from M1-like to M2-like phenotypes in the colon (An et al., 2020). Polarized M2b macrophage exosomes boosted Treg cells and suppressed pro-inflammatory cytokines, including IL-1β, IL-17A, and IL-6 (Yang et al., 2019).

DCs are antigen-presenting cells (APCs) that contain MHC-I and MHC-II molecules on their surfaces, which activate T cells (naive) and promote IBD progression (Darrasse-Jèze et al., 2009). DC-derived EVs influence IBD progression via immune regulation. Therefore, inhibition of DC activation can induce immune tolerance and regulate Treg activation. It has been documented that EVs tend to localize in the intestinal tract, specifically in association with epithelial cell adhesion molecule (EpCAM) (Chen G. et al., 2021). Inhibition of EpCAM expression in the colon exacerbates murine IBD, and the protective effect of EVs from IECs with decreased EpCAM expression on murine IBD is impaired (Jiang et al., 2016). In addition, efficient immune responses to EVs from migratory DCs require local secretion in lymphoid tissues (Lindenbergh and Stoorvogel, 2018). In summary, these findings reveal that EVs rely on specific environmental conditions to operate effectively.

2.3 EVs and intestinal barrier dysfunction in IBD

The gut must maintain tolerance to the constant foreign matter it encounters to stay balanced. Interestingly, intestinal permeability is a vital aspect in IBD etiology. The processes of intestinal barrier maintenance are altered in the inflamed gut, including downregulation of epithelial cadherin (E-cadherin), decreased mucus layer thickness, and malfunctioning of goblet and Paneth cells (Shen et al., 2022; Camilleri et al., 2012). EVs regulate epithelial cell permeability and tight junction integrity by transporting destructive or protective factors. In a healthy intestine, IECs enhance the repair of gut wall integrity by producing Annexin A1 (ANXA1)-containing EVs, an amino acid that promotes wound healing in patients (Leoni et al., 2015). The allylic hydrocarbon receptor (AHR) is an additional strategy in homeostasis regulation. Once stimulated, AHR produces IL-22, stimulates IL-10R levels, and reinforces gut epithelium’s tight junctions to preserve gut integrity (Stockinger et al., 2021). AHR also inhibits the expression of the IL-33 receptor, which is associated with the suppression of tumorigenicity 2 (ST2, strongly detected in IBD), while decreasing the synthesis of certain pro-inflammatory mediators, including IL-13. IL-13 stimulates STAT6 in epithelial cells and influences tight junctions in the intestinal epithelium (Imai et al., 2019; Chen Y. et al., 2021). IL-1β recruits granulocytes to the infection site, compromising the connectivity and integrity of gut epithelial cells (Coccia et al., 2012). IL-9 presence is also linked to changes in tight junction expression, with excessive IL-9 in the gut potentially compromising epithelial barrier integrity and tolerance to symbiotic bacteria, resulting in inflammation (Chen Y. et al., 2021). Moreover, TNF-α and IL-1β induce endoplasmic reticulum stress, affect Caco-2 cells (IECs), and significantly alter key proteins in the apical and basolateral membranes, including E-cadherin. This further disrupts the tight junctions of the intestinal epithelium (Chotikatum et al., 2018). Intestinal mucosa polymorphonuclear neutrophil (PMN) infiltration is common in IBD. Myeloperoxidase (MPO), which is released from PMNs, damages and compromises the gut barrier’s integrity. When escorted by EVs, MPO reaches the IECs, where it enhances inflammatory responses and hinders wound healing by regulating IEC migration and proliferation (Slater et al., 2017).

The control of the gut barrier is also significantly influenced by the ingesta-derived EVs. Table 1 shows how ingested EVs affect the gut barrier. In conclusion, it has been demonstrated that EVs from host cells significantly contribute to the pathophysiology of IBD by impairing the intestinal barrier and preventing the healing of intestinal wounds.

Effect on inflammationOriginSizeMajor functional component(s)OutcomeReference (s)Anti-inflammatoryBovine milk30.0–200.0 nmMultiple proteins and miRNAsModulating the TLR4-NF-κB and NLRP3 signaling pathways helps regulate intestinal immune homeostasis, restore the balance between Treg and Th17 cells, and reshape the gut microbiota.Tong et al. (2021)Grapefruit105.7–396.1 nmNaringeninIncreased HO-1 levels while lowering IL-1β and TNF-α production in colon macrophages.Wang et al. (2014)Grape343.0–418.0 nmMultiple lipids, proteins, and miRNAsInducing intestinal stem cell proliferation and intestinal tissue remodeling.Ju et al. (2013)Broccoli18.3–118.2 nmSFNActivating AMPK to induce tolerogenic DCs.Deng et al. (2017)Ginger220–290 nmLipid, protein, miRNA, and ginger bioactive constituents (6-gingerol and 6-shogaol)Preserving the gut barrier and replenishing the gut microbiota after being absorbed by IECs and macrophages.Zhang et al. (2016)

The impact of ingesta-derived EVs on the gut barrier.

EV, extracellular vesicle; miRNA, microRNA; TLR, Toll-like receptor; NF-κB, nuclear factor-κB; NLRP, Nod-like receptor pyrin domain-containing; Treg, regulatory T cell; Th17, T helper 17 cell; HO-1, heme oxygenase-1; IL-1β, interleukin-1β; TNF-ɑ, tumor necrosis factor-ɑ; SFN, sulforaphane; AMPK, adenosine monophosphate-activated protein kinase; IEC, intestinal epithelial cell.

2.4 EVs and the gut microbiota in IBD

The gut microbes definitely play an important role in intestinal inflammation (Lee and Chang, 2021). However, definitive cause–and–effect mechanistic relationships have been challenging to demonstrate outside specific animal models. Evidence from substantial experimental models indicates that although gut bacteria often drive immune activation, chronic inflammation in turn shapes the gut microbiota and exacerbates dysbiosis (Ni et al., 2017). IBD patients have a different gut microbiome than healthy individuals, as evidenced by downregulation of Firmicutes and upregulation of Bacteroidetes, Actinobacteria, and Proteobacteria, and an increase in the Firmicutes-to-Bacteroides ratio. There is also a notable decrease in intestinal flora diversity (Jacobs et al., 2016). Emerging evidence suggests that EVs derived from gut bacteria play a crucial role in the interaction between microbiota and host. For instance, F. prausnitzii, a member of the thick-walled phylum F. prausnitzii (Fp-Evs), raised the ratio of Tregs in the colon tissue of colitis mice and enhanced the protein expression of zona occludens (ZO)-1 and occludin. Fp-EVs downregulated the expression of the proinflammatory cytokines. Moreover, Fp-EV treatment markedly reduced the phosphorylation of several proteins, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK), while also regulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) (Ye et al., 2023). It is known that adherent-invasive Escherichia coli (AIEC), which is abundant in the gut mucosa of CD patients, impairs intestinal epithelial barrier stability and triggers the onset of gut fibrosis by modulating and destabilizing proteins at cell junctions, thereby increasing permeability. AIEC invasion increased the levels of IL-33 receptor ST2 in gut epithelial cells, which is necessary for the onset of gut fibrosis (Imai et al., 2019). The exosomes secreted by these infected IECs activate the host’s innate immune response and enhance intracellular replication of these pathogens. Abnormal bacterial colonization leads to inflammation by transporting microbial components via EVs. According to recent research, patients with intestinal barrier failure have a high concentration of lipopolysaccharide (LPS)-positive bacterial EVs (Tulkens et al., 2020). Besides LPS, their cargo also includes deoxyribonucleic acid (DNA), enzymes, RNA, peptidoglycan, and toxins. Their interaction with epithelial cells can regulate the gut barrier, control the proliferation and apoptosis of intestinal epithelial cells, and finally trigger the intestinal immune response (Chelakkot et al., 2018; Li et al., 2015; Kunsmann et al., 2015).

3 The role of extracellular vesicles in IBD-associated colorectal cancer3.1 EVs as promoters of tumorigenesis in the inflamed gut

The function of EVs in tumor formation, survival, advancement, and other stages of tumorigenesis remains an active area of research. Numerous studies have shown that EV-mediated signaling can promote mutagenesis during the epithelial injury-repair cycles through genomic instability and epigenetic alterations. IBD-induced damage to intestinal epithelial cells leads to the release of EVs carrying mitochondrial DNA (mtDNA). These EVs are taken up by adjacent colonic epithelial cells (CECs), where the mitochondrial genome drives metabolic reprogramming, mitochondrial respiration, and reactive oxygen species (ROS) production, thereby promoting TGFβ1-mediated tumor progression (Guan et al., 2024). During the tissue repair phase, Wnt signaling molecules carried by EVs promote cell proliferation to repair the intestinal barrier. However, under inflammatory conditions, persistent Wnt signaling activation leads to abnormal expansion of the intestinal epithelial stem cell niche (Rahmati et al., 2024). The mitochondrial transcription factor A (TFAM) mRNA carried by MSC-EVs can alleviate mitochondrial damage and inflammation by stabilizing mtDNA (Zhao et al., 2021). Patients with gastrointestinal cancers have increased levels of certain circulating EV fractions compared to those with inflammatory gastrointestinal diseases such as IBD (Deutschmann et al., 2013; Mitsuhashi et al., 2016). This may be attributed to irregular EV secretion resulting from acidic conditions and hypoxia. Tumor pH levels between 6.0 and 6.8 suggest that increased acidity correlates with greater tumor aggressiveness. This acidic environment favors cancer cells that are resistant to treatment, which in turn secrete more EVs under stress (Fais et al., 2014).

3.2 EVs and the tumor microenvironment (TME) in IBD-associated CRC

The TME is diverse, comprised of extracellular matrix (ECM), stromal tissue, and malignant cells (Lei et al., 2020). CRC cells release EVs into the TME to communicate with immune cells and their own cells. It has been shown that EVs derived from CRC can alter the TME, leading to tumor development and spread by promoting immune evasion and a cancerous phenotype in recipient cells (Figure 3) (Glass and Coffey, 2022). A study has shown that CRC cells can secrete SEVs, which are absorbed by macrophages and contain miR-21-5p and miR-200a, thereby inducing M2-like polarization and PD-L1 expression. This results in increased abundance of PD-L1 CD206+ macrophages and decreased activity of CD8+ T cells in the CRC TME (Yin et al., 2022). During cancer treatment, persistent senescent tumor cells (STCs) generate abundant EVs that are rich in serine protease inhibitor 1 (SERPINE1). SERPINE1 binds to p65, facilitating its nuclear translocation and subsequently activating the NF-κB signaling pathway, which promotes the progression of recipient CRC cancer cells (Zhang D. et al., 2024). However, tumor exosomes can activate CD4+/CD25+/Foxp3+ Treg cells via TGFβ-1, leading to immunosuppression (Ciardiello et al., 2016). The production of myeloid-derived suppressor cells (MDSCs) can inhibit the antitumor functions of T cells and natural killer (NK) cells, thereby promoting tumor progression. In another study, Zhang et al. discovered that tumor-derived EVs transfer complement C3, which induces pulmonary macrophages to release CCL2 and CXCL1. This improves macrophage polarization and facilitates the recruitment of PMN-MSCs, eventually enabling tumor spread (Zhang Y. et al., 2025). Figure 3 shows how EVs derived from CRC alter the TME, promoting tumor growth and metastasis.

EVs derived from CRC alter the TME, promoting tumor growth and metastasis. CRC-derived EVs can polarize M2 macrophages and activate Treg cells, resulting in immunosuppression. Polarized M2 macrophages can, in turn, promote EMT. The production of MDSC suppresses the anti-tumor activity of T and NK cells while allowing tumor cells to proliferate. Tumor-derived EVs circulate to distant organs and modify the ECM, boosting tumor cell adhesion and encouraging angiogenesis. TGFβ-1, transforming growth factorβ-1; Treg, regulatory T cell; miR, microRNA; MDSC, myeloid-derived suppressor cell; NK cell, natural killer cell; EMT, epithelial-mesenchymal transition; ECM, extracellular matrix; α-HSC, activated hepatic stellate cell; Gas6, growth arrest specific 6.

To sustain the survival and spread of rapidly growing malignant cells, angiogenesis is critical for supplying sufficient nutrition and oxygen (Huang et al., 2021a). Angiogenesis involves the formation of new blood vessels, which occurs when a vascular bud develops from an existing blood vessel or when a capillary wall germinates into the lumen of a blood vessel; then, columns form within this lumen. There is growing evidence that EVs are essential for angiogenesis (Wang et al., 2019; Shang et al., 2020). For instance, EVs derived from CRC perivascular cells expressed growth arrest-specific 6 (Gas6) and facilitated the recruitment of endothelial progenitor cells (EPCs) to tumors by activating the Axl pathway. This process leads to tumor revascularization after the withdrawal of antiangiogenic drugs (Huang et al., 2021b). Huang and colleagues observed that EVs from CRC cells were increased in Wnt4 in hypoxic settings. Wnt4 is a secreted protein signal from the Wnt family that plays a role in carcinogenesis (Li et al., 2014). These exosomes enriched with Wnt4 increased β-catenin nuclear translocation in endothelial cells in a hypoxia-inducible factor 1-α (HIF1α)-dependent way (Huang and Feng, 2017). However, Shang and the team discovered that CRC cell exosomes overexpressing miRNA (miR)-183-5p inhibited the proliferation, invasion, and tube formation ability of microvascular endothelial cells (HMEC-1) by upregulating forkhead box O1 (FOXO1), indicating that overexpressing miR-183-5p exosomes may be a useful therapeutic indicator for CRC (Figure 3) (Shang et al., 2020).

Tumor-derived EVs can affect tumor growth by promoting malignant cell proliferation and remodeling the ECM, where changes in composition, degradation, and stiffness are considered key contributors to tumor growth. Given their organic nutritional properties, tumor-derived EVs spread to distant organs and interact with and regulate the ECM complex, thereby increasing the adhesion of circulating tumor cells (CTCs) and paving the way for tumor cell infiltration (Kaushik et al., 2016). Since ECM dysregulation is often reported as the key step in the invasion-migration cascade, a comprehensive study of tumor cell EVs and their interactions with the ECM complex will help determine the drivers of distant organ activation and subsequent tumor invasion (Kaushik et al., 2016). An activated hepatic stellate cell (α-HSC) influences the growth and spread of CRC cells by modifying and augmenting the ECM (Figure 3) (Ahmad et al., 2003). Li and colleagues found through in vitro and in vivo experiments that the membrane glycoprotein dysadherin specifically acts on matrix metalloproteinase 9 (MMP9), enhances the invasiveness of CRC cells and the hydrolytic activity of ECM proteins, and activates cancer-associated fibroblasts (CAFs), thereby initiating ECM remodeling and amplifying cancer progression in the TME (Lee et al., 2024).

3.3 EVs and metastasis in IBD-associated CRC

The spread of tumor cells is a crucial factor in the progression of cancer. EVs are essential for EMT, creating a pre-metastatic milieu, and promoting CRC cell proliferation during metastasis (Rahmati et al., 2024). Metastases account for most of the deaths in CRC patients. The liver is the most prevalent location of metastasis, with around 30% of CRC patients acquiring hepatic metastases (Chen J. et al., 2020). This section mainly discusses the role of EV in liver metastasis of CRC.

The distinctive conversion of IECs to mesenchymal cells is known as EMT. Additionally, there is a shift towards a low-proliferation phase, and a breakdown of cell junctions and apical-basal polarity, which facilitates tumor cell movement and invasion (Pastushenko and Blanpain, 2019). After undergoing EMT, CRC cells release exosomes containing miR-106b-5p, which suppresses programmed cell death 4 (PDCD4) and activates the PI3Kγ/Akt/mTOR signaling pathway, thereby leading to M2 polarization. Conversely, M2 stem cells accelerate cancer cell motility and invasion by boosting the EMT process (Yang et al., 2021). Moreover, Liang and colleagues reported RNA pyrophosphohydrolase, a long non-coding (lnc) RNA, is significantly expressed in SW620 and HCT8 cells and physically interacts with β-III tubulin to promote malignant cell motility and EMT (Liang et al., 2019). The premetastatic niche has key features, including angiogenesis, vascular permeability, immunosuppression, reprogramming, lymphangiogenesis, organ tropism, and inflammation. These characteristics are essential for creating a favorable environment that allows malignant cells to settle and proliferate (Liu and Cao, 2016). There is evidence that upregulation of EV-mediated tissue inhibitor of matrix metalloproteinase-1 (TIMP1) in recipient fibroblasts induces ECM remodeling. However, HSP90AA, a heat-shock protein, can bind to EV-related TIMP1, thereby inhibiting TIMP1-mediated ECM remodeling, making EV-related TIMP1 a potential therapeutic target (Rao et al., 2022). Moreover, EV-associated miR-181a-5p metastasis in CRC cells with a high metastatic propensity stimulates TME remodeling, premetastatic niche development, and hepatic metastasis. This is accomplished by activating hematopoietic stem cells by inhibiting suppressor of cytokine signaling 3 (SOCS3) expression and enhancing the IL6/STAT3 pathway (Zhao S. et al., 2022).

CAFs are critical stromal cells that play major roles in tumor growth. CAFs secrete exosomes that promote CRC spread and chemotherapeutic resistance by increasing the cell’s stemness and EMT. For example, CAF cells activate the Wnt/β-catenin pathway by increasing the expression of miR-92a-3p exosomes and inhibit mitochondrial cell death by directly suppressing F-Box and WD Repeat Domain Containing 7 (FBXW7) and modulator of apoptosis 1 (MOAP1), thereby promoting cell stemness and EMT in CRC (Hu et al., 2019). EVs containing integrin beta-like 1 (ITGBL1) activate fibroblasts in distant organs by inducing the production of pro-inflammatory cytokines such as IL-8 and IL-6, ultimately promoting the growth of metastatic tumor cells (Ji et al., 2020). Furthermore, although cancer stem cells (CSCs) represent only a small portion of tumor cells, they are widely regarded as key drivers of tumorigenesis and play essential roles in shaping the tumor microenvironment and promoting metastasis. EVs derived from CSCs reportedly mediate cell crosstalk via the horizontal transfer of tumorigenic factors, such as oncogenes and proteins (van Niel et al., 2018). Studies have demonstrated that overexpression of miR-200c in CSCs leads to the release of EVs that carry excess miR-200c, thereby enhancing metastatic potential by promoting proliferation and inhibiting apoptosis (Tang et al., 2020). These results show how EVs derived from the TME affect recipient cells and play a crucial role in metastasis.

3.4 EVs as mediators of therapy resistance in IBD-associated CRC

Current chemotherapy regimens include both single-agent therapy, primarily based on 5-fluorouracil (5-FU), and multiple-agent combination medications such as oxaliplatin (OX), irinotecan, and capecitabine. Currently, the treatment of CRC still faces several challenges, such as low bioavailability of anticancer medications in the rectum and distal colon, the existence of efflux pumps in cancer cells, and the potential for medication exposure to healthy cells, which leads to adverse consequences and poor prognosis (Singh et al., 2022). Exosomes can influence drug resistance by increasing the number of efflux pumps in sensitive cancer cells. For example, overexpression of ATP-binding cassette (ABC) transporters, including ABCB1 (P-glycoprotein) and ABCC1 (multidrug resistance-associated protein), increases the release of 5-FU from malignant cells, reducing its intracellular concentration and effectiveness (Rahmanian et al., 2021). Notably, the most studied exosome-mediated mechanism of drug resistance involves the transfer of bioactive cargo via exosomes, with studies focusing on miRNA. A study attributed metastatic capacity, EMT, and 5-FU/OX resistance to CAF-derived exosomal miRNAs, including miR-92a-3p (Hu et al., 2019). Another study discovered that miR-196b-5p increases stemness and pharmacologic resistance to 5-FU in CRC cells by targeting the negative regulators of the STAT3 signaling pathway, SOCS1 and SOCS3 (Ren et al., 2017).

The involvement of EVs in drug resistance is a new research domain. Therefore, EV-mediated cargo selective delivery to cancer cells is an effective strategy to improve the therapeutic index and overcome drug resistance. For instance, sorafenib overcomes irinotecan resistance in CRC by increasing ibrutinib’s toxicity and promoting intracellular accumulation by blocking the drug-excreting pump ABCG2 (Mazard et al., 2013). EVs can also enhance targeted drug delivery, regulate immunological responses, and interact with the TME to make malignant cells more susceptible to therapy. However, long non-coding RNA (lncRNA, LINC01915) limits the use of EVs derived from CRC by normal fibroblasts (NFs) through the miR-92a-3p/Krüppel-like factor 4/cholesterol 25-hydroxylase (miR-92a-3p/KLF4/CH25H) pathway. This mechanism prevents angiogenesis and the transformation of NFs into CAFs, thereby inhibiting tumor growth (Zhou et al., 2021). In another study, CRC cells expressing IL-33 showed increased 5-FU sensitivity when T cells were present, thereby activating intrinsic apoptosis and signals associated with immunological destruction of tumor cells (Song et al., 2023). In TME, higher levels of milk fat globule-epidermal growth factor 8 (MFGE8) promote efferocytosis by stimulating macrophages to remove cisplatin-induced apoptotic cells, contributing to the lethal consequences of chemotherapeutic resistance (Ma et al., 2024). These findings shed fresh light on the potential synergistic use of chemotherapeutic drugs, EV inhibitors, and cell proliferation inhibitors in CRC therapy.

4 Novel inflammatory mediators: their interaction with extracellular vesicles in IBD and CRC4.1 Specific examples of novel inflammatory mediators and their EV-mediated transport and regulation

In IBD, novel inflammatory mediators activated by EVs, such as DAMPs, non-coding RNAs, metabolic intermediates, and specialized pro-resolving mediators (SPMs), are transmitted to epithelial cells and the TME to convey pro-tumor inflammatory signals, as evidenced by numerous specific examples (Figure 4).