Introduction

Breast cancer (BC) is the most common cancer among women in most countries, with the highest mortality and morbidity rates [1]. Despite the earlier detection and improved clinical management, there is still a high death rate among women because of treatment failure and metastasis [2]. BC can be divided based on its molecular characteristics into luminal A, luminal B, HER2, estrogen, and progesterone-positive receptors, and triple-negative BC (TNBC). Further subcategories of TNBC include basal-like 1 and 2, immunomodulatory, luminal androgen receptor, mesenchymal, and mesenchymal stem cell-like [3, 4]. TNBC and HER2-positive breast cancers are more likely to metastasize to other areas of the body, such as the brain, bone, lung, liver, and abdominal cavity [5, 6].

In recent decades, there has been a dramatic increase in the literature associated with the involvement of the immune system in BC [7]. It is well known that the immune system plays an important role in the development, progression, and control of BC [8]. The complex relationship between the immune system and cancer cells is characterized by the theory of “cancer immunoediting” (CI) [9], which was initially developed by Dunn et al. [10] CI postulates a dual role of the immune system in cancer: host-protective and tumor-promoting actions [11]. CI consists of “three Es”: elimination, equilibrium, and escape [12, 13]. In the ‘elimination’ phase, all tumor cells may be destroyed by the immune system [13]. During the second phase, the opposing forces remain balanced and cancer growth is still under control. Escape is the terminal stage of immunoediting, in which cancer cell variants effectively evade immune pressure, replicate progressively, and become clinically apparent [13]. In light of this, manipulating the immune system and boosting its defenses against cancer may be one of the keys to controlling cancer [14]. This idea is known as cancer immunotherapy [14]. Exosomes (Exo) have emerged as potential sources of biomarkers for early detection and prognosis in breast cancer. Several studies have identified specific molecules, such as proteins, nucleic acids, and microRNAs, within exosomes that show promise as diagnostic and prognostic markers. MiRNAs are small non-coding RNA molecules that regulate gene expression. For example, miRNA-21, miRNA-155, and miRNA-210 have been found to be upregulated in breast cancer-derived exosomes and are associated with tumor growth, metastasis, and poor prognosis [15,16,46]. However, under certain conditions, the biogenesis of exosomes can occur via an ESCRT-independent pathway. This process can be mediated by lipids such as ceramides and cholesterol [47].

Exosomes participate in several normal and pathological conditions, such as pregnancy, immune responses, cardiovascular disorders, viral pathogenesis, neurological disorders, and cancer [48]. According to the origin of the donor cell, exosomes play a variety of roles, including immune response, antigen presentation, programmed cell death, angiogenesis, inflammation, coagulation, etc. [27, 49] (Figure1).

Fig. 1
figure 1

Exosome Biogenesis in the Source Cell, Uptake, and Cargo Transfer (a) Exosome Biogenesis in the Source Cell: The intracellular mechanisms involved in exosome biogenesis within the source cell are depicted in this area of the image. It displays the early endosome formation process, the sorting of different cargo molecules into the develo** exosomes, and the inward budding of the endosomal membrane to generate multivesicular bodies (MVBs). Labeled cargo molecules consist of proteins, RNAs (miRNAs and mRNAs), lipids, and other bioactive compounds. (b) Exosome Uptake Routes by Target Cells: This portion of the diagram shows the various ways that target cells can absorb exosomes. It demonstrates a variety of exosome uptake processes, including as receptor-mediated interactions, membrane fusion, and endocytosis. (c) Cargo Transfer and Impacts in the Target Cell: The cargo transfer that occurs when exosomes enter the target cell and the ensuing impacts are the main topics of this portion of the picture. It shows how certain cellular processes are activated and how exosome cargo is released into the target cell’s cytoplasm

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TDEs effect on immune cells

Over the past 10 years, the study of exosomes has observed increasing attention, representing a high-potential area for their application in cancer as biomarkers and therapeutic tools [50]. Tumor-derived exosomes (TDEs) are important immune adjusters in the tumor milieu. TDEs reduce immune cell cytotoxicity in the microenvironment of tumor cells by transporting suppressive cargo to these cells, to facilitate tumorigenesis [51]. TDEs have been implicated in all stages of BC progression (tumor initiation, growth, dissemination, and metastatic spread) [2]. As part of their immunological functions, exosomes modulate antigen presentation, immune activation, immune surveillance, intercellular communication, and immune suppression [52, 53]. On the other hand, the expression of PD-1 on the surface of BC-derived exosomes can blunt T-cell activation, effectively enabling tumor cells to escape immune surveillance [84].

Precision BC treatment has been significantly improved by nanoparticle-based technology. Exosomes are natural nanoparticles carrying chemotherapeutic drugs, photosensitizers or antitumor drugs. For cancer therapy, exosomes are particularly appealing drug delivery system due to their excellent biosafety, low immunogenicity, carrier properties, and nanoscale penetration effect [Drug delivery carriers

Exosomes can be utilized to transfer conventional clinical chemotherapy drugs to targeted sites, thus reducing their toxicity and improving their enrichment effect [126]. Tran et al. loaded aspirin, as an anti-cancer agent, into exosomes that enhanced drug dissolution and homing targeting effect. Aspirin-loaded exosomes exerts cytotoxicity effects on breast and colorectal cancers [127]. Yu et al. showed that erastin-loaded exosomes labeled with folic acid suppressed the proliferation and migration of MDA-MB-231 cells and induced ferroptosis through the depletion of intracellular glutathione and activation of ROS [88]. In another study, exosomes loaded with paclitaxel (PTX) inhibited tumor progression of MDA-MB-231 cells and were considered an effective drug delivery carrier for BC [128].

Doxorubicin (DOX), a common chemotherapeutic remedy for breast cancer, has been shown to decrease the risk of relapse by up to 8% and death by 6.5%. However, the side effects of congestive heart failure and medicine resistance necessitate switching patients taking doxorubicin to fewer effective therapies. Tian et al. engineered immature DCs (imDCs) expressing Lamp2b, an exosomal membrane protein, fused to αv integrin-specific iRGD peptide. Exosome derived from imDCs loaded with DOX and targeted to αv integrin- positive BC cells. iRGD exosomes efficiently inhibited tumor growth without noticeable toxicity [129]. Li et al. introduced milk exosomes containing DOX to the BC cells with specifically CD44-targeting hyaluronic acid (HA). The HA-mExo-Dox effectively targeted CD44-expressed BC cells and induced apoptosis in vitro [130]. Additionally, Hadla and colleagues confirmed that, in comparison to the free drug, DOX-encapsulated exosomes had less of an impact on cardiac toxicity and other tissues. As a result, the dose of DOX can be enhanced, resulting in a targeted cytotoxic effect on breast cancer cells [126].

Clinical implications

Achieving an optimal balance between maximal effectiveness and minimum side effects for conventional drugs used to combat tumors is often difficult due to tumor heterogeneity and biological barriers. Many anti-cancer agents in clinical practice have poor bioavailability and little in vivo stability, causing adverse damage to normal cells. Technologies based on exosomes offer exciting approaches to diagnosing and treating BC. Therapeutic agents can be delivered more efficiently using nanoplatforms, which are innovative dosage forms. Besides uploading drugs, nanoplatforms have the ability to target active molecules as well [131].

Nanoplatforms are mainly used to target tumors by enhancing the permeability and retention (EPR) of tumor internals or by interacting with antigens overexpressed on tumor surfaces. A unique carrier property and biosafety make exosomes ideal for develo** precisely targeted approaches. In this review, current methods of exosomes in BC treatment are discussed specifically, but there are several challenges to overcome. The production and isolation methods need optimization to obtain sufficient quantities of exosomes with consistent quality and purity. Standardization of isolation, characterization, and quality control methods is crucial for safety and reproducibility. Determining the best administration route is challenging, and different routes need evaluation for effectiveness and safety. Achieving targeted delivery to specific tissues or cells is difficult, but strategies like engineering exosomes with specific ligands are being explored. Loading therapeutic cargo into exosomes is challenging due to limited capacity, and efficient methods are needed for stability and preservation. Exosomes from different cell sources may have varying immunogenicity profiles, so minimizing immune responses is important. Lastly, long-term safety and potential off-target effects or accumulation concerns require careful evaluation [132, 133].

However, through genetic editing, researchers can precisely manipulate specific genes to increase or decrease their expression, thus enhancing anti-tumor exosome production. Exosome surface modification during nanocarrier production can improve exosome recruitment and abundance at tumor locations as well as the recognition of a specific target. Additionally, chemotherapeutics and other therapeutic chemicals like phototherapy and photothermal therapy can be delivered using exosomes as a delivery vehicle. On the other hand, the majority of the current studies involve cell and animal research, and are now in the preclinical stage. It is required to do extensive research on the creation of exosome carriers, how they actually work in the human body, and the management of side effects to establish the combination of both the efficacy and safety of exosome delivery as a way to finally achieve clinical use.