Exosomes in cancer: Functional mechanisms and therapeutic perspectives

Abstract

Exosomes are nano-sized extracellular vesicles that play a key role in intercellular communication. Due to their low immunogenicity, good biocompatibility, and tumor-targeting ability, they have shown great potential in cancer therapy. Their applications mainly include three aspects: Exerting direct antitumor effects through their endogenous cargo, serving as engineered drug delivery systems, and functioning as immunomodulators or cancer vaccines. In particular, exosomes derived from mesenchymal stem cells (MSCs) have been widely studied; however, their impacts on tumors are dual-sided, acting as either promoters or inhibitors depending on the context. This minireview summarizes the mechanisms of exosomes in cancer therapy, highlights the bidirectional role of MSC-derived exosomes, and discusses their clinical translation prospects.

Key Words: Exosomes; Cancer therapy; Drug delivery; Immunomodulation; Mesenchymal stem cells; Tumor microenvironment

Core Tip: This minireview elucidates the triple roles of exosomes in cancer therapy: As direct effectors, drug delivery vehicles, and immunomodulators. Focusing on mesenchymal stem cell-derived exosomes as a paradigm, it details their context-dependent, “double-edged sword” functionality in tumor regulation. The discussion extends to key translational challenges, including cargo complexity and manufacturing standardization, while highlighting engineering strategies as the critical path toward harnessing exosomes as potent, cell-free therapeutics.

INTRODUCTION

Exosomes are nanosized membrane-coated vesicles secreted by a wide range of cell types[1]. With a typical diameter of 30-150 nm, exosomes carry diverse cargo-including plenty of proteins, nucleic acids, lipids, and other bioactive molecules, which makes them a critical mediators of intercellular communication[2]. Exosomes are involved in a variety of physiological and pathological processes. In recent years, exosome-based cancer research has grown rapidly, covering areas such as direct tumor suppression, drug delivery, and immunotherapy[3,4]. Among various cellular sources, exosomes derived from mesenchymal stem cells (MSCs) are regarded as particularly promising natural nanocarriers, due to their ready availability, low immunogenicity, and tumor-homing capacity. Given their translational relevance and well-documented functional complexity, this article reviews the multifaceted roles of exosomes in cancer therapy, focusing on MSC-derived exosomes to illustrate the multifaceted and dual roles of exosomes in cancer therapy.

DIRECT ANTITUMOR EFFECT OF EXOSOMES

Exosomes play a multifaceted role in regulating the tumor microenvironment, angiogenesis, tumorigenesis, metastasis, and resistance to chemo- and radiotherapy. In many cases, exosomes can directly influence tumor behavior by transferring functional molecules. On one hand, tumor-derived exosomes often promote malignancy[5]. For example, glioma-derived exosomes under hypoxia induce M2 macrophage polarization, trigger autophagy and facilitate tumor progression[6]; exosomal miRNA-23a from nasopharyngeal carcinoma promotes angiogenesis by inhibiting TSGA10[7]; exosomes from tumor-associated macrophages convey miR-589-3p, which promotes the development of ovarian cancer[8]; exosomes derived from bladder cancer stem cells can enhance the stemness and chemotherapy resistance of bladder cancer cells by delivering LUCAT1[9]; and exosomal miRNA92a-3p from cancer-associated fibroblasts enhances chemoresistance in colorectal cancer via the Wnt/β-catenin pathway[10].

On the other hand, some exosomes exert tumor-suppressive effects. For instance, exosomes carrying miRNA-let7e inhibit migration and invasion in non-small cell lung cancer[11]; exosomes from Plasmodium-infected mice suppress lung cancer angiogenesis by downregulating VEGFR2[12]; and MSC-derived exosomes deliver tumor-suppressive miRNAs such as miR-3940-5p, miR-22-3p and miR-16-5p, inhibiting invasion and progression in colorectal and endometrial cancers[13-17]. In addition, radiotherapy increases the production of exosomes and enhance the expression of miR-3160-5p within the exosomes, which inhibits pancreatic cancer progression[18]. These findings highlight that the functional outcome of exosomes-whether promotive or suppressive-is determined by their specific bioactive cargo. Consequently, appropriately increasing specific genes or substances within exosomes, that is, utilizing exosomes as effective carriers, is a hotspot in the field of exosome-based tumor therapy.

EXOSOMES AS DRUG DELIEVERY SYSTEMS

Compared to synthetic nanocarriers, exosomes offer superior biocompatibility, low immunogenicity, and high stability. Their lipid bilayer membrane protects encapsulated drugs or nucleic acids from degradation, making them ideal delivery systems in clinical field. For instance, dendritic cell (DC)-derived exosomes loaded with tumor peptides can eradicate tumors in vivo, leading to clinical trials as early as 2005[19]. Similarly, MSC-derived exosomes carrying siRNA targeting KRASG12D are being evaluated in pancreatic cancer patients[20].

Furthermore, the presence of native surface proteins and ligands enables exosomes to recognize and bind specific cells or tissues, providing an inherent targeting capacity for precise drug delivery. This intrinsic targeting can be further enhanced through bioengineering techniques[21]. Moreover, their bilayer lipid structure helps minimize off-target effects on healthy tissues, which is particularly significant for cancer therapy. In chemotherapy, exosomes can deliver chemotherapeutic drugs such as paclitaxel and doxorubicin, enhancing antitumor efficacy and reducing systemic toxicity[22-24]. Zhang et al[25] utilized MSC-derived exosomes as a delivery system for a triple-drug combination (galectin-9 siRNA/DOGEM/indocyanine green), which substantially enhanced the synergistic effect of chemotherapy, immunotherapy, and phototherapy on pancreatic cancer. Compared to macromolecular drugs, RNA molecules are highly susceptible to degradation, making their delivery a major challenge. By using exosomes as carriers, these small RNA molecules can be shielded and delivered intact to target cells, significantly enhancing their bioavailability and therapeutic efficacy[26-29]. For instance, exosomes carrying the RUNX3 DNA (a key gene for lung adenocarcinoma) could significantly target cancer cells and induce their apoptosis[30]; exosomes derived from miR206-overexpressing tumor cells exhibited antitumor efficacy in colorectal cancer mice by modulating the intercellular interactions, the gut microbiota, and the immune microenvironment[31]; MSC-derived exosomes delivering miR-499a-5p and miR-26a-5p inhibit the migration, invasion, and tumor growth of endometrial cancer by targeting VAV3[32,33]. With their natural tumor-targeting properties and highly efficient delivery, exosomes have been positioned as a next-generation delivery platform for cancer therapy. To translate this potential into clinical application, key translational challenges, including standardized manufacturing, efficient cargo loading, and rigorous clinical validation-must be addressed. Future development should focus on engineering exosomes tailored to tumor-specific biomarkers, offering a versatile new modality for targeted cancer treatment.

EXOSOMES IN TUMOR IMMUNOMODULATION

Exosomes play a dual role in tumor immunology: They can mediate immunosuppression but can also be engineered for immune activation[34]. Tumor-derived exosomes function as potent immunosuppressive mediators that promote immune escape through multiple mechanisms. A key example is their carrying of immune checkpoint molecules such as programmed death ligand-1, which directly inhibits T cell function[35,36]. Their broad suppressive impact involves inducing T cell apoptosis, impairing the differentiation and maturation of DC, and inactivating natural killer (NK) cells. Furthermore, these exosomes actively shape a pro-tumorigenic microenvironment by enhancing the proliferation of regulatory T cells (Tregs) and regulatory B cells (Bregs), polarizing macrophages toward the immunosuppressive M2 phenotype, and expanding the population of myeloid-derived suppressor cells[5].

Conversely, immune cell-derived exosomes tend to enhance antitumor immunity. For example, DC-derived exosomes expressing MHC and co-stimulatory molecules promote T cell activation and tumor rejection[37]; NK cell-derived exosomes exert cytotoxic effects via miR-186 or induce apoptosis through perforin, granzyme B[38,39]; and T cell-derived bioactive exosomes exert Fas ligand-mediated cytotoxicity[40]. Additionally, exosomes carrying miR-423-3p inhibit M2 macrophage polarization, thereby suppressing cervical cancer growth[41]. These findings underscore the potential of exosomes as immunomodulatory agents in cancer treatment. Consequently, a key goal in the field is to shift the exosomal balance from tumor-promoting to immune-activating, by neutralizing detrimental exosomes and redirecting their natural delivery system for therapeutic purposes. The triple roles of exosomes on cancer therapy were illustrated in Figure 1.

Figure 1  Triple roles of exosomes in cancer therapy.

MSC-DERIVED EXOSOMES: A DOUBLE-EDGED SWORD

MSCs are a prolific and most important source of exosomes. MSC-derived exosomes possess excellent biocompatibility and tissue penetration, but their effects on tumors are context-dependent[42,43]. Some studies show that MSC exosomes promote tumor progression and therapy resistance. For example, exosomal miR-106a-5p from MSCs promotes accelerates triple-negative breast cancer progression[44]; the lncRNA LINC00461 from MSC exosomes contributes to multiple myeloma pathogenesis[45]; MSC exosomes enhance resistance to 5-FU in gastric cancer by activating the CaM-Ks/Raf/MEK/ERK signaling cascade[46]; and exosomes from bone marrow-derived MSCs in acute myeloid leukemia and chronic myeloid leukemia are associated with resistance to tyrosine kinase inhibitors[47,48].

However, many other studies confirm that MSC-derived exosomes inhibit tumor growth and improve responses to chemo- and radiotherapy. For instance, exosomes from human umbilical cord MSCs carrying miR-375 inhibit the proliferation, invasion, and migration of esophageal cancer cells[49]; miR-503-3p and miR302a in human umbilical cord blood MSC exosomes inhibit endometrial cancer progression[16,17]; adipose tissue-derived MSC exosomes delivering miR-122 enhance sorafenib efficacy in hepatocellular carcinoma[50]; and MSC-derived exosomes transfected with miR34c inhibit the invasion, migration, proliferation, and epithelial-mesenchymal transition of nasopharyngeal carcinoma while reducing radioresistance[51]. Therefore, the application of MSC-derived exosomes must be carefully evaluated based on tumor type and molecular context. Ultimately, MSC-derived exosomes constitute a complex, context-dependent signaling network rather than a simple delivery vehicle. Harnessing their full potential requires a nuanced understanding of the molecular switches that dictate their dual roles. The future of this field lies in learning to decode these signals and programmatically engineer exosomes-or the MSCs that produce them-to ensure a reliably therapeutic outcome against cancer.

CLINICAL TRANSLATION AND CHALLENGES OF EXOSOMES IN CANCER THERAPY

Despite the considerable promise of exosomes in cancer treatment, no exosome-based therapeutic has yet received full market approval, and the field remains in an active phase of clinical translation. Several engineered exosome-based strategies have advanced into early-stage clinical trials. For instance, building on promising preclinical results that demonstrated enhanced tumor retention and systemic anti-tumor immunity with minimal systemic inflammation[52], the exoSTING platform utilizes engineered exosomes to deliver STING agonists precisely to antigen-presenting cells within the tumor microenvironment, activating anti-tumor immunity. This candidate is currently under evaluation in a phase I/II trial (NCT04592484) for advanced solid tumors. In another study, curcumin encapsulated in exosomes was investigated for its effects on immune modulation and cellular metabolism in patients undergoing surgery for colon cancer (NCT01294072). Such studies provide preliminary evidence of safety and potential efficacy.

However, significant challenges must be addressed to enable broad clinical application. On the production front, establishing scalable manufacturing processes that comply with Good Manufacturing Practice is essential to ensure batch-to-batch consistency in exosome yield, purity, and function. Regarding quality control, standardized analytical methods for critical attributes-such as particle size, drug loading, and biological potency-are urgently needed. Furthermore, key translational and regulatory gaps remain, including a clearer understanding of in vivo pharmacokinetics, long-term safety profiles, and defined regulatory pathways for these complex biologics. Moving forward, advances in closed bioreactor systems, refined engineering strategies, and rigorously designed clinical studies will be crucial to translate exosome-based therapies from promising experimental agents into practical clinical tools.

CONCLUSION

As a natural information transfer system, exosomes play multifaceted roles in cancer therapy. They can directly affect tumor cells, serve as efficient drug carriers, and regulate antitumor immunity. MSC-derived exosomes, with their low immunogenicity and tumor-targeting capacity, are of particular translational interest, though their functional duality demands careful investigation. The clinical translation of exosome-based therapies, while promising, remains at an early stage, facing challenges in scalable manufacturing, standardization, and regulatory clarity. Future studies should focus on precise engineering and functional standardization of exosomes to develop safe and effective therapeutic agents in oncology.