Breast cancer (BC) accounts for more than half of all cancer-related deaths in women globally and is the most often diagnosed kind of the disease (F et al., 2018). In addition to causing a serious blow to patients’ quality of life and economic burden, BC is also a significant public health risk due to an increased prevalence and incidence of BC mortality among women. The global BC epidemic has been estimated at 1.6 million new cases per year with more than 50% of these being newly diagnosed. BC accounts for approximately 30% of all cancers diagnosed in developed countries and 40% in developing countries, including India, China, Brazil, South Africa, and Mexico (Sung et al., 2021). In the actual clinical setting, the primary therapies for BC consist of endocrine therapy, targeted medication therapy, chemotherapy, surgical resection, and so forth (Jayaraj et al., 2019). Some studies have found that several immunotherapy drugs have shown good efficacy in clinical trials, but they are not widely used in clinical practice (Schmid et al., 2018). Nevertheless, medication resistance and a dearth of biomarkers for monitoring therapeutic response could occasionally make therapies less effective. Therefore, it is essential to understand the potential biological mechanisms underlying pharmaceutical resistance and to hunt for reliable biomarkers to predict and monitor therapy response.

Extracellular vesicles (EVs) are tiny membrane vesicles that exist outside of the cell formed by cells that transport a range of functional nucleic acids, proteins, and lipid cargos required for intercellular communication. (Sedgwick and D’Souza-Schorey, 2018; Maacha et al., 2019; Sedgwick and D’Souza-Schorey, 2018; Mao and Jin, 2019). The dual invagination of the plasma membrane and the development of intracellular multivesicular bodies (MVBs) that contain intraluminal vesicles (ILVs) result in the production of these exosomes. ILVs are finally discharged as exosomes through exocytosis and MVB fusion to the plasma membrane, with sizes varying from around 40–160 nm. The classification of EVs is in a constant state of flux, but they are generally split into two major collectives: ectosomes and exosomes. The former includes the EVs, which can be found in the plasma membrane; and intracellular vesicles, which may contain proteins that can bind to receptors on cells, such as adhesion molecules or cytokines. The latter include endoplasmic reticulum-bound proteins, including cytochrome oxidase, proteases, enzymes involved in glycolysis and other metabolic reactions, and cell surface markers (Cocucci and Meldolesi, 2015). Ectosomes are vesicles with dimensions ranging from ∼50 nm to 1 μm that are produced when the plasma membrane buddes straight outward, creating microvesicles, microparticles, and large vesicles. Conversely, though, exosomes originate from endosomes and are in a size range of ∼40–160 nm in diameter (100 nm on average) (Kalluri and LeBleu, 2020). Schematic representation of the exosome production process has shown in Figure 1.

Increasing evidence has pointed to a newly identified mechanism that causes medicine resistance called exosome-mediated cell communication (Maacha et al., 2019; Goh et al., 2020). Exosomes directly export drugs, cause inactivation of drugs, and transfer functional proteins and noncoding RNAs, all of which contribute to resistance to BC. However, the role of exosomal drug transport mechanisms in resistance to BC has not yet been elucidated (Giallombardo et al., 2016; Ender et al., 2019). Different sources of exosomes enter recipient cells through endocytosis. This process has three different mechanisms (Kalluri and LeBleu, 2020): 1). The ‘cargo’ of the exosomes is discharged into the cytoplasm and reformed into multivesicular bodies after they enter the recipient cells. 2). Exosomes ‘cargo’ is released into the cytoplasm but fuses in conjunction with the plasma membrane. 3). Exosomes can transport ‘cargo’ into the cell by endocytosis when their ligands attach to certain receptors on the receptor cell membrane.

The capacity of infiltration and migration in BC is one of their traits that influences tumor patient survival and may even result in mortality. Breast tumor cells can spread to different places in the body using a variety of molecular mechanisms and pathways (Rashid et al., 2021; Tan et al., 2021; Wang et al., 2021b). BC metastasis is caused in various ways. For instance, the BC drug has-circ-0068631 engages EIF4A3 and causes c-Myc signaling to increase BC metastasis (Wang et al., 2021a). There are elements that prevent BC migration and invasion. CST6 peptides and protein inhibit CTSB activity to prevent BC from encroaching into bone (Li et al., 2021b). In clinical courses, focusing on variables related to BC metastasis has proven helpful (Hou et al., 2021). It has been demonstrated that extracellular Hsp90α promotes lymph node invasion in BCers and that cancer metastasis can be inhibited by employing the appropriate antibody (Hou et al., 2021). NFE2L3 downregulation (Dai et al., 2021). It has been proposed that overexpressing MTA1 increases BC metastasis. FOXP3 inhibits MTA1 expression to decrease the spread of BC (Liu et al., 2021). Consequently, a number of molecular mechanisms influence the regulation of BC metastasis (Guo et al., 2021; Li et al., 2021a; Yang et al., 2021b; Zuo et al., 2021). Some strategies have been used in impairing BC invasion. For example, element nano-emulsions reduce the spread of breast carcinoma cells by inducing reactive oxygen species (ROS) scavenging (Han et al., 2021). Anti-cancer agents such as alkaloid derivative ION-31a (Ni et al., 2021) and adducing formula (Yang et al., 2021a) can suppress BC metastasis by affecting autophagy and Hsp90α. The mechanisms behind the epithelial-to-mesenchymal transition (EMT) and how they impact the growth of breast tumor cells are the subject of the following sections.

In cancer, up to 90% of deaths are due to drug resistance in humans, and the number is still increasing It has reached a level where there will be no cure for cancer at this moment (Łukasiewicz et al., 2021). Chemotherapeutic medications are less effective when there is multi-drug resistance (MDR), which frequently results in metastasis and relapse. About half of individuals who are resistant to drugs have either acquired or innate resistance (Wang et al., 2019b). The development of new therapies which can overcome these resistance mechanisms is crucial to achieving a cure for cancer. Three factors can cause intrinsic resistance to emerge before therapy does: genetic alterations, the expansion of pre-existing insensitive fractions (such cancer stem cells), and the natural defense against dangerous external substances (Holohan et al., 2013). Alternatively, acquired resistance may result from activation of proto-oncogenes, changes in gene expression due to mutations or epigenetic marks as well as changes in the tumor microenvironment following treatment (Holohan et al., 2013). There are several mechanisms of resistance in BC, which includes increased drug efflux, enhanced DNA repair, senescence escape, epigenetic modifications, tumor heterogeneity, tumor microenvironment (TME), and EMT (Holohan et al., 2013; Cosentino et al., 2021; He et al., 2021). Exosomes play a significant and particular role in the management of BC resistance. More details are as follows.

Chemotherapy is one of the most common treatments for invasive BC, especially triple-negative breast cancer (TNBC). To avoid cell death brought on by chemotherapeutic medicines, BC cells can, nevertheless, use several strategies. These processes mostly involve drug efflux and inactivation (Dallavalle et al., 2020), activation of bypass signaling or pro-survival pathways, enhancement of DNA damage repair (Battista et al., 2020), and induction of EMT (Navas et al., 2020) and stem-like property. In terms of tumors, tumor-derived exosomes (TDEs) are involved in regulating tumor growth, invasion, drug resistance, angiogenesis, immune evasion, and remodeling of the tumor microenvironment (Wan et al., 2020). Furthermore, a great deal of research has shown that the cell stress brought on by anticancer therapy altered the makeup of exosomes secreted by tumor cells. Treatment resistance may arise from drug-resistant phenotypes spreading throughout BC tumor cells (Lv et al., 2014a).

Targeting the estrogen receptor (ER), which is present in large quantities in roughly 70% of BC patients, is an available hormone therapy (Muluhngwi and Klinge, 2017; Brufsky and Dickler, 2018). Endocrine therapy has increased the number of ER-positive BC patients who survive without developing a disease, however, the clinical problem of BC metastasis or recurrence brought on by endocrine resistance has not yet been resolved. There have been several research on the mechanisms of endocrine medication resistance, mostly concentrating on somatic cell alterations, epigenetics, and tumor microenvironment, but the precise mechanisms are still not completely understood. The mechanism of endocrine resistance is generally understood to be quite complex. Many ER-blocking medications are currently on the market and are often utilized in the therapeutic treatment of individuals with ER + BC. One such drug is tamoxifen (TAM), which can successfully shut down ER activation and downregulate the growth of ER + tumors (Early Breast Cancer Trialists’ Collaborative Group EBCTCG, 2011). However, the growth of cancers that gain hormonal resistance after prolonged treatment frequently renders hormone therapy in BC ineffective in BC (Osborne and Schiff, 2011; Rani et al., 2019). The mechanism of hormone resistance is the subject of extensive research. The resistance to hormones primarily arises from dysregulation of estrogen receptors, the activation of several pathways and an imbalance between activators and inhibitors (Osborne and Schiff, 2011; Scherbakov et al., 2012; Muluhngwi and Klinge, 2017; Semina et al., 2018). The ER plays a crucial role in regulating several physiological processes, such as immune system responses (including autoimmune response), metabolism, reproduction, cell proliferation, and many other functions. In short, exosomes could transfer the acquired hormone resistance of BC cells primarily through the following mechanisms: activation of hormone-independent pathways and ER dysregulation caused by exosomal miRNA and protein. Only a handful of studies have demonstrated the transfer of hormone resistance between BC cells. Therefore, more investigation is needed to examine the proteome and non-coding RNA profiles of exosomes released by hormone-resistant BC, as well as to identify the critical elements for the exosome-mediated transmission of the hormone-resistant phenotype. Treatment resistance and exosomes in British Columbia for human epidermal growth factor receptor 2 (HER2) overexpression of HER2 was associated with a poor prognosis for BC (Cortesi et al., 2015). When used in clinical practice, HER2-targeted treatment effectively treats HER2+ BC (Tagliabue et al., 2010). The first monoclonal HER-2 antibody approved for the treatment of HER2+ BC is trastuzumab (Cameron et al., 2017), which dramatically prolongs patients’ lives. Trastuzumab is safe and effective in multiple trials with good safety profiles. However, there are several potential adverse events associated with trastuzumab, such as severe nausea, vomiting, rash, and diarrhea. These side effects may not occur when used together with other anti-HER2 drugs or therapies that affect the immune system. Within a year of finishing treatment, the majority of patients become resistant to HER2-targeted medications, despite the fact that BC patients initially respond well to these treatments (Ahmad, 2019). Figure 3 depicts an illustration of the membrane transport pathway involved in the creation and release of multivesicular endosomes, as well as the resistance mechanism of HER2 targeted therapy.

According to certain research, Antibody-based drugs are neutralized by exosomes, which results in BC trastuzumab resistance (Dong et al., 2020). HER2-targeted medication resistance is tightly correlated with levels of programmed death ligand 1 (PD-L1) and transforming growth factor β1 (TGF-1) (Devan et al., 2022). According to Martinez et al. (Martinez et al., 2017), they discovered that these chemicals are transferred by EVs to cause drug-sensitive cells to exhibit the traits of their source cells. Trastuzumab resistance could also be a result of non-coding RNA dysregulation. RNA-binding protein heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was discovered to be crucial for lncRNA AGAP2-AS1 loading into exosomes (Alarcón et al., 2015). Additionally, by examining the Gene Expression Omnibus database’s publicly accessible BC miRNA expression profiling data, Han et al. (Han et al., 2020) discovered that trastuzumab resistance resulted in a downregulation of miR-567 expression. They then found that trastuzumab resistance was caused by miR-567 suppression, but exosomal miR-567 reversed trastuzumab resistance by inhibiting autophagy-related (Lappano et al., 2020). Therefore, these observations highlight the special role that exosomes play in promoting resistance to targeted therapy, either through direct interactions between HER-2 overexpressed exosomes and targeted agents, or through exosome-mediated transcription changes that promotes cell survival through the HER2-independent pathway.

A new chapter in the treatment of cancer has begun with the recent success of innovative anti-cancer immunotherapies (Zhang and Zhang, 2020). Previously, it was thought that bladder cancer, melanoma, and lung cancer were more immunogenic than BCs (Sugie, 2018). According to recent research, TNBC tumors are more immunogenic than other BC subtypes, with higher levels of lymphocyte filtrating and PD-L1 expression (Barroso-Sousa et al., 2020). Which significantly lengthens patients’ lives. Multiple trials with positive safety profiles have demonstrated the efficacy and safety of trastuzumab. However, Trastuzumab has several possible side effects, including severe nausea, vomiting, rash, and diarrhea. When combined with other anti-HER2 medications or immune system-affecting therapy, these side effects might not manifest. (Michel et al., 2020). On 8 March 2019, the FDA granted accelerated clearance for the anti-PD-L1 medication atezolizumab plus nab-paclitaxel for unresectable locally advanced or metastatic TNBC with PD-L1 expression, based on the findings of the IMpassion 130 trial. However, there is still much work to be done in order to achieve the best effect of BC immunotherapy. In addition, it is urgent to discover and apply new biomarkers to predict the response to immunotherapy. Exosomes are crucial for changing the tumor immunological microenvironment. According to reports, tumor cells could have PD-L1, and exosomal PD-L1 prevents T-cell activation, which could help cancer cells avoid antitumor immunity (Chen et al., 2018a). Furthermore, it appears that anti-PD-L1 antibodies cannot completely inhibit exosomal PD-L1. In Poggio et al. study, has shown that the exosome PD-L1 was expressed in cells of human lung epithelium and mediates cell migration through a mechanism similar to the mechanisms of the proteasome, which might lead to increased expression of PD-L1 (Poggio et al., 2019). However, PD-L1 expression varies and changes over time in various BCs. It is known that among the many BC subtypes, basal-like BC cells express the greatest PD-L (Soliman et al., 2014). According to Moneypenny et al. (Monypenny et al., 2018), in BC cells, the endosomal sorting complex required for the transport-related protein ALIX controls the activation of the PD-L1’s surface expression and the epidermal growth factor receptor. This finding suggested that MSCs were a promising model for studying the mechanisms underlying BC and its complications. A recent study has shown that the expression of CD56 on B cells is down. They found that PD-L1, which confered a more immunosuppressive characteristic on BC cells, was more prevalent on the surface of ALIX-depleted cells. Additionally, Wen et al.'s research (Wen et al., 2016) has shown which exosomes are obtained directly from BC cells that have spread far reduced NK activity and T cell proliferation, possibly limiting the anticancer immune response in pre-metastatic organs. Additionally, another study has shown that TGF--mediated inhibition of T cell proliferation by exosomes derived from BC cells (RONG et al., 2016). However, the development of cancer and the resistance to immunotherapy are both significantly influenced by tumor-associated macrophages. Exosomes produced by mesenchymal stem cells (MSC) were found by Biswas et al. (Biswas et al., 2019)to hasten the course of BC. As a result, type 2 macrophages polarize myeloid-derived monocyte-suppressive cells into highly immunosuppressive macrophages near the tumor bed. This finding suggested that MSCs were a promising model for studying the mechanisms underlying BC and its complications.

These findings have significant ramifications for our comprehension of the fundamental mechanisms driving immunosuppression in BC’s TME. To sum up, exosomes transport immunosuppressive chemicals that have been widely investigated in various cancers and are known to impact immune cell activities in a variety of ways. Since the majority of immunotherapy research for BC is still being done at the time of the clinical trial, exosome-mediated immunosuppression is currently being examined, and it needs more research. Exosomes could be used as a prognostic biomarker that may eventually be employed as a non-invasive method to track the effectiveness of immunotherapy in malignancies. Recent studies have shown that EV release characteristics were generally associated with cellular phenotypic modification, such as EMT. Exosomes regulate EMT, cancer stem cell (CSC), and TME in the drug resistance of BC (Fujiwara et al., 2018b; Fujiwara et al., 2018a) and CSC (Eguchi et al., 2018; Hu et al., 2019). EMT and stemness encourage cells to release EVs, and tumor-derived EVs mayactivate EMT and stemness in tumor cells (Eguchi et al., 2020). As a result, the EMT and CSC characteristics are anticipated to favor both exosome-mediated tumor progression and the development of treatment resistance.

Numerous research over the past few decades have shown that the TME had a significant role in determining both treatment resistance and tumor growth, progression, and metastasis (Brown and Giaccia, 1998; Matei et al., 2017; Taube et al., 2018; Vasan et al., 2019; Lappano et al., 2020). EMT is a biological process in which epithelial features are lost and a mesenchymal phenotype is acquired (Bill and Christofori, 2015). During the course of EMT, some biochemical changes occur in cells, including loss of strong cell-cell adhesion and development of invasive, migratory, and antiapoptotic properties. The major effector molecules are the transcription factors that regulate gene expression (i.e., genes involved in apoptosis or DNA damage). Exosomes are a crucial part of the EMT process that results in a more aggressive phenotype for cancer cells. A growing body of research suggests that exosomes may be capable of delivering pro-EMT factors to recipient cells, promoting the development of BC, chemoresistance, invasion, metastasis, and anti-apoptosis, among others (Qin et al., 2016; Donnarumma et al., 2017; Santos et al., 2018; BIGAGLI et al., 2019). According to Liu et al. (Liu et al., 2015), the miR-155 is an essential EMT regulator and CSCs. Santos et al. (Santos et al., 2018) has reported that the upregulation of EMT was linked to miR-155 in DOX- and PTX-resistant cells. In addition to these effects, transfected miR-155 cells also drive EMT. Some authors reported that miR-155 expression was increased in the presence of DOX and PTX, suggesting a direct role for miR-155 in tumor progression.

Furthermore, immune cells, including myeloid-derived suppressor cells, mast cells, neutrophils, lymphocytes, and macrophages, DCs, and NK cells have been demonstrated to be permeable in the TME (Whiteside, 2016). Exosomes, which carry tumor-associated antigens, interfere with anti-tumor immunotherapy. Exosomes are produced by these cells to transmit information regarding immunosuppression or activation. On the basis of the research reported above, exosomes could be produced by TME cells in response to anticancer therapies and promote TME-to-BC cell interaction that leads to the transmission of drug resistance. Exosomes could be as tumor biomarkers that reflect TME alterations and predict therapeutic response, according to all of these studies. Drug resistance directionally transferred between TME and BC cells through exosomes has shown in Figure 4. The researchers believed that the use of exosomes could help identify new targets for treatment and develop new cancer therapies.

Exosomes is a “double-edged sword” in the treatment of BC drug resistance. The most common characteristics of malignant tumors are invasion and metastasis. Invasion and metastasis are multi-step processes that involve “crosstalk” between tumor cells and normal cells around the tumor at each stage. Exosomes, as one of the intercellular communication carriers, can directly transfer messenger RNA, miRNA, and proteins into cells and activate related signaling pathways, boosting tumor invasion and metastasis. To summarize, on the one hand, exosomes can induce drug resistance in BC; on the other hand, exosomes constitute a significant breakthrough in the treatment of BC drug resistance.

Exosomes have many application scenarios in the treatment of BC drug resistance. Firstly, exosomes are a type of EV that exist in the circulation system. Exosomes exist in all biological fluids and are secreted by all cells. They could be applied to the dynamic measurement of a variety of biological components related to tumor drug resistance, and have the unique potential to monitor the dynamic complexity of cancer. The biogenesis of exosomes can capture complex extracellular and intracellular molecules and can be used for comprehensive, multiparametric diagnostic assays. The surface proteins of exosomes also contribute to their immune capture and enrichment. Secondly, exosomes also have the potential to serve as candidate biomarkers for predicting and monitoring treatment effects in BC patients. Thirdly, the property of exosomes to deliver functional substances to diseased cells facilitates their use as therapeutic vehicles and as potential targets or transporters for reversing drug resistance. As a drug carrier, liposomes are a new type of targeted preparation that has been clinically applied earlier and is the most mature. Compared with liposomes, exosomes have a lower immune clearance rate. In addition, exosomes have been proven to be well tolerated and have no obvious side effects, opening up a new way to treat BC. Currently, exosomes have good prospects in treating BC drug resistance and treating drug resistance in other tumors, but there are also some difficulties. First, although there are many sources of exosomes, traditional extraction methods are insufficient to identify specific exosomes (Akagi et al., 2015). In this regard, it is necessary to find efficient, fast, and economical methods to clarify the source of exosomes, and more clinical studies are needed to verify the effectiveness and safety of current strategies for exosomes to deal with drug resistance in BC. At present, there are few clinical research reports on BC exosomes. In recent years, people have paid more and more attention to the function of exosome genes, but the relevant mechanisms have not been fully elucidated. Since conventional drugs are unavailable in many cases or patients develop an immune response to tumor cells after surgery, molecular targeted therapy may be an effective option for unstable cancer cells. Molecular targeted therapy can achieve cure by inducing the body’s own production of anti-exosome antibodies. However, there is no complete definition yet because this technology has some limitations: first, the method requires a long time and a lot of effort and high cost; secondly, exosomes may enhance the side effects of drugs and tumor cells of drug resistance. In addition, in most cases, exosomes must be controlled by specific gene expression products to function. However, currently, there are no systematic reports on the expression and metastasis of exocrine hormone receptor-binding proteins in tumors.

In summary, the study of exosomes is an active area of research and additional studies in the future may yield valuable information on their heterogeneity and biological functions and enhance the ability to exploit their therapeutic and diagnostic potential, Provide more ways and ideas for clinical treatment of BC drug resistance and other research fields. I believe that soon, it will bring good news to many cancer patients.