Exosomes were first described in the 1980s as membranous vesicles in reticulocytes (35). Initially, exosomes were considered cellular garbage, withal later studies have shown that exosomes can transfer genetic information to achieve cell-to-cell communication (36). The biogenesis of exosomes mainly involves three stages: first, the fusion of endocytic vesicles produces early endosomes (EEs), which encapsulate the cargo of endocytic cells that share certain biomolecules and membrane proteins; second, the late endosomes (LEs) are composed by the inward sprouting of the multivesicular body (MVB) membrane; finally, MVB can fuse with lysosomes or autophagosomes for degradation, which can also fuse with the plasma membrane to release the contained substances, namely exosomes (37, 38). They are encased in lipid bilayers and carry various biological molecules, such as RNA, DNA, proteins, glycans, and lipids (39). Many studies revealed that exosomes are rich in ncRNA (40). ncRNAs can bind to recipient target cells through exosome carriers to transmit information and change the gene expression and function of recipient cells, thus affecting cancer progression to a certain extent (34, 41).

Exosome-derived ncRNAs are involved in driver mutations and epigenetic modifications that drive various pathophysiological processes in CRC (42). A large number of studies on exosomes have shown that exosomal ncRNAs communicate throughout cancer and non-cancer cells and are closely involved in the occurrence and development of CRC (43, 44). Moreover, studies have shown that exosomes are much easier to take up by cancerous cells than other vesicles of an equal amount, indicating that exosomes have a higher selectivity for cancer targeting (45). We particularly focused on the roles of miRNAs, lncRNAs, and circRNAs in the TME of CRC ( Table 1 ).

One of the distinguishing characteristics of cancer is its ability to stimulate angiogenesis (84). In practice, TME needs to provide more oxygen and nutrients as the tumor continues to grow (23). During this process, TME sends signals to endothelial cells, causing an increase in the expression of mutiple angiogenic factors in order to form a new blood vessel (85). In particular, vascular endothelial growth factor (VEGF) is a powerful angiogenic factor that is widely recognized as a critical element in angiogenesis (86). VEGF regulates vessel formation by binding to VEGF receptors (VEGFRs)-1, -2, and -3, which are expressed on vascular endothelial cells (87). To create innovative anti-angiogenic medicines, it will be necessary to have a deeper knowledge of the cellular and molecular pathways that are involved in tumor angiogenesis.

Abnormal expression of exosomal ncRNAs impact cancer progression through regulating angiogenesis (88). He et al. found that miR-21-5p is propagated from CRC cells to recipient human umbilical vein endothelial cells (HUVECs) via exosomes, then activated β-catenin signaling pathway, increased downstream target expression, and regulated CRC angiogenesis and vascular permeability (89). In another study suggested significant upregulation of CRC cell-derived exosomal miR-1229 suppressed HIPK protein expression and activated the VEGF pathway of HUVECs. Moreover, exosomal miR-1229 inhibitor substantially inhibited tumor growth and angiogenesis as demonstrated by a nude mouse xenograft model (90). Zeng et al. showed that cancer-derived exosomal miR-25-3p drives CRC development by altering the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells through targeting KLF2 and KLF4 (91). Likewise, the STAT3/VEGFR-2 signaling axis was activated by CRC cell-derived exosomal miR-221-3p, which promoted endothelial cells angiogenesis (92). Shang et al. discovered that miR-185-3p was significantly expressed in cancer cell-derived exosomes and overexpression of its target gene FOXO1 could reverse the increase in angiogenesis-related proteins caused by miR-183-5p in HMEC-1 cells (93). Chen et al. revealed that cancer cells derived exosomal miR-27b-3p trafficking into vascular endothelial cells reduced VE-Cad and p120 expression, increased vascular permeability in vivo, and eventually accelerated CRC metastasis (94). These studies demonstrate that exosomal ncRNAs affect angiogenesis and permeability to promote colorectal tumor metastasis.

Tumor-associated immune cells are a part of the TME, which play an important role in the TME and may have tumor-promoting or opposing effects (95, 96). Dunn et al. proposed the “cancer immunoediting” theory, which is based on the dual role of immunity in the complex interaction between tumor and host (97). In short, the immune system has the ability to prevent tumor development and progression while suppressing its occurrence and development (96, 97). However, some initial tumors can evade this attack and continue to develop in the host, increasing their chances of metastasis and recurrence (98). Interactions between immune cells and cancer cells, as well as exosome-related intercellular communication, are vital in tumor immune regulation, producing an immunosuppressive environment that promotes cancer development and progression (99).

Multiple studies demonstrate that exosomal ncRNAs mediate complex interactions between tumor and immune cells and induce changes in the expression of genes that regulate immunosuppression, confirming the functional significance of exosomal ncRNAs in immune modulation (100, 101). Another study showed that exosomal circPACRGL generated from CRC cells promoted neutrophil N1-N2 differentiation through the miR-142-3p/miR-506-3p-TGF-β1 axis (102). Moreover, the immune system normally responds to foreign antigens by promoting the proliferation and differentiation of cytotoxic T cells in TME (103). Xian et al. found that overexpression of exosomal lncRNA KCNQ1OT1 secreted by CRC cell affected cytotoxic T cells by regulating PD-L1 ubiquitination via miR-30a-5p/USP22, leading to immune escape (104). Similarly, exosomes ncRNAs can potentially serve as a bridge between tumor cells and NK cells, facilitating the exchange of information. For instance, exosomal lncRNA SNHG10 derived from CRC cells contributed to immune escape by suppressing NK cell function by upregulating INHBC expression as well (105).

Macrophages are innate immune cells that play a variety of roles in host defense and tissue homeostasis in TME (106). Exosomes have also been found to affect the pre-metastatic niche and promote cancer metastasis by altering the localization and function of tumor-associated macrophages (TAMs) through related mechanisms (11, 107, 108). Wang et al. found that when CXCL12/CXCR4 axis is activated, CRC cells produce exosomal miRNAs (miR-25-3p, miR-130b-3p, and miR-425-5p), which macrophages may take up and ​target PTEN through activation of PI3K/Akt signaling pathway, resulting in the M2 phenotypic transfer. Crucially, M2-polarized macrophages in turn secrete VEGF, which promotes CRC angiogenesis and liver metastases (109). Zhao et al. showed that tumor-derived exosomal miR-934-induced M2 macrophage polarization promotes CRC liver metastasis through activation of the CXCL13/CXCR5 axis (110). Meanwhile, another study found that CRC cell-derived exosomal lnc-RPPH1 promotes CRC cell metastasis and proliferation in vivo through mediating macrophage M2 polarization by binding to TUBB3 (111).

These studies confirmed that exosomal ncRNAs can alter the immunological microenvironment via influencing immune cell phenotypic.

In addition, reprogramming of energy metabolism is also seen as a hallmark of cancer (84). Glycolysis is the primary source of energy metabolism in tumors and obtains more sugar breakdown capacity, which can convert glucose into lactate to generate ATP, resulting in the formation of an acidic TME that is more conducive to cancer growth (112). Tao et al. found that exosomal miR-101-3p targeted and decreased HIPK3 expression in CRC cells, reduced mitochondrial membrane potential and produced reactive oxygen species (ROS), while increasing aerobic glycolysis and encouraging colorectal tumor development (113). Exosomal circ_0005963 from drug-resistant cells were delivered to drug-sensitive cells to inhibit glycolysis via the circ_0005963/miR-122/PKM2 pathway (114). Moreover, exosomes can mediate communication between cancer cells and adipocytes, which facilitate the transfer of nutrients such as lipids in the TME (115). Exosomal miR-146b-5p was released by cancer cells to promote browning of white adipose tissue (WATs) and increase lipolysis. Further study indicated that exosomal miR-146b-5p inhibited HOXC10 overexpression to increase WAT browning, reduce oxygen consumption and regulate lipolysis (116).

Furthermore, the nutritional status of oxygen has a substantial impact on cancer’s ability to use energy, and differences in energy storage between normoxic and hypoxic cells present various transfer potentials in the TME (117). Exosomal circ-133 generated from Hypoxic cells was transported into normoxic cells and promoted CRC metastasis by acting on the miR-133a/GEF-H1/RhoA axis (117). Yang et al. found that CAFs-derived exosomal circEIF3K was delivered to CRC cells and promoted CRC progression by regulating the miR-214/PD-L1 axis in the hypoxic microenvironment (118). According to these studies, targeting exosome cargoes that govern energy metabolism might provide a novel and successful method for cancer therapy.

Exosomal ncRNAs are involved not only in cancer progression and metastasis, but also in treatment resistance development (119). Obviously, one of the challenges in the treatment of tumor processes during chemoradiotherapy is the development of drug resistance. Exosomes present important mediators of intercellular communication, may contribute to the horizontal spread of drug resistance in heterogeneous cancer cell populations, which might make it impossible to treat many cancers effectively (120).

Methotrexate (MTX) is an antineoplastic drug that is widely used as standard chemotherapy in the treatment of various malignancies (121). Under MTX treatment, downregulation of the CDX2/HEPH axis by CAFs-derived exosomal miR-24-3p inhibitor accelerates the resistance of colon cancer cells to MTX (122). Recently, studies have demonstrated that exosomal miR-208b promotes regulatory T cells (Tregs) expansion by targeting PDCD4, and exosomal miR-208b upregulation was the most pronounced in oxaliplatin-resistant cells. That may be associated with reduced oxaliplatin-based chemosensitivity in CRC (123). Exosomal miR-208b can thus be employed as an oxaliplatin treatment response indicator. CAFs delivered exosomal lncRNA CCAL to cancer cells inhibited apoptosis in CRC cells, activated the β-catenin pathway, and promoted oxaliplatin resistance both in vitro and in vivo (70). Hon et al. found that exosomal circ-0000338 can transfer chemoresistance from FOLFOX-resistant cells to sensitive cells (124).

Furthermore, CRC patients who are undergoing chemotherapy commonly develop resistance to the drug 5-fluorouracil (5-FU) (125, 126). Similarly, overexpression of exosomal miR-181d-5p suppressed 5-FU sensitivity of CRC cells (127). According to Hu et al., exosomal miR-92a-3p was shown to be considerably higher in 5-FU/L-OHP resistant CRC patients than in 5-FU/L-OHP sensitive CRC patients. Further research found that CAFs-derived exosomal miR-92a-3p transfer to CRC cells then promoted the Wnt/β-catenin pathway, directly inhibited FBXW7 and MOAP1 to suppress mitochondrial apoptosis, which affects cancer growth and medication resistance (128). In addition, Ren et al. discovered that exosomal lncRNA H19 acted as a competitive endogenous RNA sponge for miR-141 to activate the Wnt/β-linked protein pathway, hence increasing resistance to oxaliplatin in CRC cells (129). These results implied that exosomal miRNAs might be as useful biomarkers for the development of CRC metastases and chemoresistance.

The above-mentioned evidence revealed that using exosomal ncRNAs to induce tumor cell resistance to anticancer drugs, cancer-associated cells were reprogrammed in the TME. We can determine that exosomal ncRNAs can also be potential therapeutic targets for overcoming drug resistance, thereby contributing to cancer patients.

CRC can be a preventable and treatable disease, and with current treatment, early diagnosis can greatly improve five-year survival rates (130). Biomarkers in bodily fluids can help identify the presence of cancer, metastasize and assess the response of treatment. Apparently, the methods of obtaining bodily fluids are significantly less invasive than traditional biopsies (131). Since exosomes can be detected in all bodily fluids and are produced by all cells, exosomes are great liquid biopsies that can be used to track the progression of sickness over time (37). Moreover, exosomal ncRNA is stable, abundant, reproducible and disease-specific, which lays the foundation for the early diagnosis of CRC (132, 133).

Min et al., found that miRNAs in exosomes, such as Let-7b-3p, miR-139-3p, miR-145-3p and miR150-3p, can be used as biomarkers for early diagnosis of CRC and have been validated in large cohorts (134). Besides, they had more discriminative power for multiple miRNA-binding diagnoses than for single miRNA-binding diagnoses (134). Moreover, high level of exosomal miR-19a expression in serum suggest the possibility of CRC recurrence (64). Pan et al. screened circ-0004771 as a potential diagnostic biomarker for CRC, and the ROC curve area of circ0004771 can distinguish benign intestinal diseases (BID), stage I/II CRC patients, and healthy controls (HCs) (135). Zhao et al. studied the exosomes taken from the plasma of CRC patients and discovered that the more severe the CRC patients, the lower the expression of miR-193a and the higher the expression of let-7g (136). Exosomal circR1 had specificity in CRC diagnosis and was associated with overall survival. In addition, the combination of exosomal circLPAR1, CEA, and CA19-9 enhanced the AUC value to 0.875 (137). As reported by Gao et al., CRC patients with high serum lncRNA 91H expression levels were generally at a higher risk of tumor recurrence or metastasis than other patients. Furthermore, CRC recurrence or metastasis can be predicted by detecting serum exosomal lncRNA 91H (138).

The above examples all demonstrate the potential and possibility of exosomal ncRNAs in various aspects, such as differential diagnosis, prognostic diagnosis, and staging characteristics.

Numerous studies have established that exosomes serve crucial biological functions in cancer growth. Therefore, specifically targeting exosomes may be a promising therapeutic approach. Interfering with CRC progression by modulating exosome expression or blocking its transport pathway may be a therapeutic strategy.

Exosomes, with their lipid bilayer structure, can delivery anti-tumor chemicals to target cells, so as to achieve the effect of treatment (139–141). Researchers have packaged interfering RNAs and chemical drugs into exosomes through various methods and targeted transport to specific cells (142, 143). This engineered exosome technology can achieve the purpose of treating disease areas or cells. Tian et al. targeted exosomes by intravenous injection to specifically deliver doxorubicin (DOX) to tumor tissue in nude mice to inhibit tumor growth (144). Bagheri et al. created a MUC1 aptamer-modified exosome for DOX administration and showed promising efficacy in reducing colorectal tumor development in vivo, laying the groundwork for the use of exosomes in preclinical cancer treatment (145). Asadirad et al. found that exosomes carrying miR-155 could stimulate bone marrow-derived DC cells to release inflammatory factors IL-12p70 and IFN-γto achieve anti-CRC effect (146). Furthermore, Zhan et al. designed exosomes as a nanoplatform capable of precisely delivering drugs and miR-21i to tumor cells, and animals treated with this technique showed increased tumor suppression without severe adverse effects (147). Liang et al. used exosome engineering to deliver the combination of miR-21 and the chemotherapeutic drug 5-FU to recipient cells, which effectively overcame drug resistance and increased the cytotoxicity of 5-FU-resistant colon cancer cells (148). With the continuous refinement and diversification of engineered exosome technology, the exosomal drug delivery system holds a lot of promise for use in the medical field as a natural nanoscale drug delivery platform.

Taken together, the potential applications of exosome-derived ncRNAs in cancer therapy are not limited to these aspects. Their roles in TME have great potential and application prospects in the future.