Chloride intracellular channel 1 (CLIC1) is an ion channel that is significantly related to drug resistance in gastric cancer cells (Ma et al., 2012). By isolating exosomes from the supernatant, Zhao et al. (2019) found that CLIC1 expression was higher in vincristine-resistant cell lines than in common GC cell lines. This proves that exosome-mediated transfer of CLIC1 can induce the development of vincristine resistance.

P-glycoprotein (P-gp) is a drug efflux pump reliant on energy regulated by the human ABCB1 gene and genes such as MDR1 (Lv et al., 2014). To make the drug effective, anti-tumor medications must reach the cytoplasm or nucleus. Tumor cells are able to encapsulate drugs as exosome cargo or secrete them out of the cell using P-gp. Blocking P-gp with calcium ion blockers can effectively prevent the efflux of anti-tumor drugs, thereby increasing the concentration of intracellular tumor drugs (Luo et al., 2013). Lv et al. (2014) found that the P-gp content of drug-resistant MCF-7/DOC was significantly higher than that of sensitive MCF-7/S, which indicated that tumor cells could induce chemotherapy-sensitive tumor cells to tolerate drugs by transferring P-gp.

LncARSR is an RNA activated in sunitinib-resistant renal cell carcinoma (RCC). It induces the expression of c-MET and AXL in RCC, which facilitates the resistance of Sunitinib by binding to miR-34/miR-449 competitively. Sunitinib resistance can be propagated by incorporating LncARSR into exosomes and delivering them to sensitive cells. Targeted nucleic acid therapy of sunitinib-resistant RCC against lncARSR or AXL/c-MET inhibitors restores the sunitinib response (Sun et al., 2018). The exosome-mediated circVMP1 delivery system has a similar effect. CircVMP1 targets the miR-524-5p-METTL3/SOX2 axis to promote cisplatin resistance in tumor cells, transmitting malignant features and cisplatin resistance to cisplatin-sensitive non-small cell lung cancer (NSCLC) (Xie et al., 2022). Analogously, microRNA-301b-3p from mesenchymal stem cells (MSCs) is delivered to chemotherapy-sensitive cells via exosomes to promote gastric cancer (GC) resistance by targeting TXNIP (Zhu et al., 2023). Wang et al. suggested that the knockout of the adipocyte-associated exosome LOC606724 or SNHG1 in adipocytes promotes the apoptotic effects of chemotherapy agents in multiple myeloma (MM) cells. MM cells facilitate LncRNA incorporation into adipocyte exosomes via methylation of LncRNA m6A mediated by METTL7A, leading to further resistance to MM (Wang et al., 2022a). In another experiment, exosomes from oxaliplatin-resistant colorectal cancer (CRC) cells delivered ciRS-122 to sensitive cells. Upregulation of miR-122 sponge and PKM2 promotes glycolysis and drug resistance. Moreover, miR-122 can target pyruvate kinase, thereby reducing the drug sensitivity of chemotherapy-sensitive cells (Wang et al., 2020a). Similarly, exosomes associated with oral squamous cell carcinoma (OSCC) induce drug resistance in tumor cells by upregulating the expression of mir-155 (Kirave et al., 2020). Liver cancer-related extracellular vesicles mediate drug efflux, thereby increasing chemotherapy drug resistance in hepatocellular carcinoma (HCC) by translocating Rab7402B (Li et al., 2020b). By downregulating miR-579-3p, circpar3-loaded exosomes induce resistance to cisplatin in the lateral population of nasopharyngeal cancer cells (Ai et al., 2023).

Since exosomes from cancer cells express cancer-associated cell surface proteins that sequester the substance away from the target cell, they obstruct antibody and medication therapy. For example, B-cell lymphoma cell-associated exosomes carry CD20, which binds to therapeutic anti-CD20 antibodies to deplete complement. This process protects lymphoma cells from antibody attack (Aung et al., 2011). Additionally, tumor-reactive antibodies are bound and sequestered by tumor exosomes to reduce their binding to breast cancer cells (Battke et al., 2011; Bach et al., 2017) (Figure 1).

The generation of harmful lipid peroxides in an iron-dependent way is the cause of ferroptosis (Lei et al., 2022; Tong et al., 2022; Zhao et al., 2022). Anti-tumor drugs such as erastin block the entry of extracellular cystine into cells by inhibiting system Xc activity. This process blocks the synthesis of glutathione (GSH) in cells, weakens the oxidation resistance of cells, and eventually leads to ferroptosis (Chen et al., 2021a). Exosomes derived from NSCLC cells transfer miR-4443 to susceptible cells, conferring cisplatin resistance. Cisplatin-induced FSP1-mediated ferroptosis is inhibited by the overexpression of miR-4443 (Song et al., 2021). The researchers highlighted that the lung cancer-associated exosome circRNA101093 (cir93) regulates arachidonic acid (AA) by maintaining an increase in cir93 in lung adenocarcinoma (LUAD) cells. cir93 interacts with and increases fatty acid-binding protein 3 (FABP3). FABP3 transports AA and enhances its response to taurine, leading to a reduction in AA and the induction of chemotherapy drug tolerance (Zhang et al., 2022a). Through Zhang et al.’s investigation, these tests revealed that exosome miR-522 secreted by GC-related fibroblasts can lead to the inhibition of ALOX15. It might lessen the buildup of lipids in tumor cells to prevent ferroptosis of tumor cells, finally leading to reduced chemotherapy sensitivity (Zhang et al., 2020). Cancer-associated fibroblasts (CAFs) were found to inhibit ferroptosis and promote the chemoresistance of pancreatic ductal adenocarcinoma (PDAC) cells after gemcitabine (GEM) treatment by secreting exosomes miR-3173-5p (Qi et al., 2023). Ferroptosis provides a new direction for antagonizing tumor drug resistance. Du et al. (2021) constructed exosomes functionalized with CD47. The researchers used ultrasound to effectively load siderosis inducers into exosomes to accelerate HCC’s ferroptosis process and provide anti-tumor effects (Du et al., 2021).

One study showed that miR-182-5p was markedly upregulated in the exosomes of glioblastoma in a hypoxic environment. VEGFR accumulates as a result of direct inhibition of its target Kruppel-like factors 2 and 4 by exosome miR-182-5p. It induces tumor angiogenesis. The structure of the newly formed vessels is unstable, and blood flow may be rapid, which makes it difficult for the drug to effectively cross the tumor vascular network, thereby limiting the drug’s reach to the tumor tissue and reducing its concentration within the tumor (Li et al., 2020c). At the transcriptional level, circPDK1 secreted by pancreatic cancer-associated exosome packaging can be activated by HIF1A, and the BPTF/c-myc axis is activated by miR-628-3p (Lin et al., 2022). Additionally, researchers discovered that the stronger oncogenic proteins STAT3 and FAS are present in exosomes of ovarian cancer cell lines grown in hypoxic environments, which dramatically increases in vitro cell motility and invasion as well as chemotherapy resistance (Dorayappan et al., 2018). Similar responses have been shown in breast cancer (BC) (King et al., 2012; Jung et al., 2018; Hannafon et al., 2019; Tian et al., 2021; Xi et al., 2021), HCC (Matsuura et al., 2019; Yu et al., 2019; Wang et al., 2022b; Yu et al., 2022; Jia et al., 2023), pancreatic cancer (Patton et al., 2020; Chen et al., 2022; Lin et al., 2022), GC (Du et al., 2020; Xia et al., 2020), CRC (Ren et al., 2019b; Li et al., 2021; Sun et al., 2021; Wu et al., 2023), and prostate cancer (PC) (Deep et al., 2020).

Critical processes in the formation of exosomes, such as vesicle budding and cargo sorting, are adversely impacted in an anoxic environment (Bister et al., 2020; He et al., 2022). Furthermore, hypoxia can affect ubiquitination proteins and ubiquitination-related enzymes, affecting the sorting of exosomal proteins. Ubiquitin proteins can accumulate through the ubiquitin-binding domains of ESCRT-0 and ESCRT-II within the multi-vesicular endosome microdomain. This process limits the number of membranes available for exosome formation, which affects exosome volume (van Niel et al., 2018; Jiang et al., 2022). In a study of PC patients, plasma from tumor patients showed higher levels of exosomes and lower volumes of exosomes. Smaller exosomes are readily able to pass through physiological barriers and enter more cells. Smaller exosomes may travel more readily through the bloodstream to the site of metastasis with this variation, which weakens the effect of drug therapy (Logozzi et al., 2021). Studies have shown that the sugar mixture on the surface of tumor-associated exosomes is highly specific (Zheng et al., 2020; Zhang et al., 2022b). The endocytosis mechanism of exosomes is sensitive to hypoxia. More exosomes can be absorbed by hypoxic cells reliant on proteoglycans (Cerezo-Magaña et al., 2021). In conclusion, modifications to plasma membrane glycoproteins brought about by hypoxia may enhance the drug resistance of tumor cells.

Epithelial–mesenchymal transformation (EMT) of tumor tissues promotes drug-resistant cell survival. Cancer cells’ enhanced plasticity enables non-genetic adaptation to drug tolerance. Under tyrosine kinase inhibition (TKI), EMT is connected to the survival of drug-resistant cells in EGFR-mutated NSCLC (Remon et al., 2018). Exosome miR-663b secreted by cervical cancer cells directly targets the 3′-untranslated region (3′-UTR) of monoacylglycerol acyltransferase 3 (MGAT3) and participates in the process of EMT transformation. Exosome miR-663b-induced metastasis of ovarian cancer cells is inhibited by MGAT3 overexpression. At the same time, exosome miR-663b can be enucleated by cervical cancer cells, which affects the survival of drug-resistant cells (You et al., 2021). The GC-associated exosome circ133 acts on the miR-133a and RhoA axes. Circ133 promotes cancer by disinhibiting its target SIX1. Interestingly, the target SIX1 reduced the sensitivity to chemotherapy in BC cells by increasing the TGFβ signaling pathway (Micalizzi et al., 2009). Moreover, GC-associated exosomes induce the transcription of ZEB1 to regulate the differentiation of CRC cells and induce drug resistance (Ono et al., 2012). CRC-associated exosomes promote EMT and increase the intracellular accumulation of oxaliplatin by delivering miR-128-3p. They have the potential to improve drug sensitivity and reduce drug resistance, serving as novel biomarkers (Liu et al., 2022a).

Exosomes promote tumor angiogenesis through various mechanisms that have antagonistic effects on anti-angiogenic drugs and eventually lead to drug resistance. Exosome miR-204-3p induces vascular endothelial cells to form tubular forms via the ATXN1/STAT3 pathway. TAK-981 has a function in inhibiting SUMOylation. It prevents tumor growth and angiogenesis by blocking miR-204-3p′s exosome sorting process. Glioma cells can accelerate angiogenesis by upregulating SUMOylation and eliminating the inhibitory factor miR-204-3p under hypoxia (Guo et al., 2023b). OSCC cells have upregulated miRNA-210-3p to promote tumor growth by increasing tumor grade and microvascular density. Ephrin A3 expression is mechanically downregulated by the exosomal miRNA-210-3p to activate the PI3K/Akt axis. The process increases angiogenesis and advances OSCC (Wang et al., 2020c). Analogously, the high migratory potential of nasopharyngeal carcinoma cells is associated with angiogenesis. Exosome miRNA-23a inhibits the production of TSGA10 by binding to its 3′-UTR. MiRNA-23a leads to angiogenesis and increases metastasis in nasopharyngeal carcinoma (Bao et al., 2018). Exosome lncRNA may also play an essential role in regulating angiogenesis. For example, exosomal miRNA-29-3p downregulates the expression of PTEN, and the inactivated PTEN signaling pathway promotes the phosphorylation of PI3K/Akt, which promotes angiogenesis in lung cancer (Cheng et al., 2019). Angiogenin-2 (ANGPT2) is believed to promote angiogenesis by disrupting vascular stability. HCC cells can secrete exosomes containing ANGPT2. These exosomes are introduced into umbilical vein endothelial cells by intracellular action, and elevated expression of ANGPT2 causes angiogenesis and encourages drug resistance (Xie et al., 2020) (Figure 2).

Wu et al. measured RNA levels in lapatinib-resistant BC specimens and then highlighted that exosomes may be a means of delivering Circ-MMP11. The knockdown of circ-MMP11 promotes lapatinib sensitivity by inhibiting cell survival and invasion while promoting apoptosis in lapatinib-resistant BC cells (Wu et al., 2021b). In Liu’s study, cancer-associated fibroblasts of LUAD secreted a long non-coding RNA, LINC01614, by exosome packaging. This RNA directly interacts with ANXA2 and p65 to promote NF-κB activation, with the glutamine transporters SLC38A2 and SLC7A5 being overexpressed, eventually enhancing glutamine influx in cancer cells. Alterations in glutamine metabolism increase the antioxidant capacity of cells and reduce their susceptibility to drug-induced apoptosis (Liu et al., 2022b).

In previous studies, researchers have suggested that cancer stem cells (CSCs) are inherently resistant to chemotherapy-induced cell death. After chemotherapy treatment, fibroblast-derived conditioned medium (CM) promoted the proportion of CSCs (CD133+ and TOP-GFP+) and tumor viability. Further studies have shown that exosomes isolated from CM have similar effects described above (Ren et al., 2018; Hu et al., 2019). Correspondingly, through the METTL3/miR-181d-5p axis, METTL3 decreases the susceptibility of CRC cells to 5-fururacil (5-FU) and enhances exosome miR-181b-5p in CAFs (Pan et al., 2022).