The incidence and mortality rates of pancreatic cancer (PC) have been steadily increasing; there were 441,000 cases of PC worldwide in 2017, compared with only 196,000 cases in 1990 (1). According to epidemiological data, PC has the lowest 5-year relative survival rate among all solid tumors, estimated at ~13% (2). Surgical resection combined with adjuvant chemotherapy represents the current standard of care and the most widely adopted clinical strategy for the treatment of PC (3). However, due to the asymptomatic nature of early-stage PC, the majority of patients are diagnosed at an advanced stage. Consequently, only a small subset of patients remains eligible for surgical intervention (4). Furthermore, the development of chemotherapy resistance, often resulting from prolonged treatment, notably impacts both the survival and quality of life of patients with PC. The pathogenesis of PC remains incompletely elucidated; however, in addition to modifiable risk factors such as smoking, alcohol consumption, obesity and diabetes, genetic mutations, familial inheritance and a complex tumor microenvironment (TME) are also recognized as critical contributing factors (1,5,6). The TME of PC is a complex ecosystem composed of cancer cells, stromal cells, immune cells and various extracellular components. PC cells actively drive genetic mutations; stromal cells produce abundant collagen and extracellular matrix leading to tissue fibrosis and highly expressed inflammatory factors create a pro-inflammatory environment. This unique TME establishes a robust foundation for the growth and metastasis of PC (7). Therefore, deepening the understanding of the molecular mechanisms underlying PC, developing more effective therapeutic strategies and overcoming chemotherapy resistance represent critical research directions that require further exploration.

Mesenchymal stem cells (MSCs) are multipotent stem cells characterized by high differentiation potential and strong self-renewal capacity, which originate from the mesoderm and ectoderm during early development (8). Studies have indicated that MSCs actively participate in the progression of PC, including tumor growth and metastasis of cancer cells, as well as the modulation of TME (9–11). Studies have reported that MSCs can promote the progression of PC by secreting pro-tumorigenic factors (12) and differentiating into cancer-associated fibroblasts (CAFs) (13). However, other evidence suggests that MSCs can also suppress the development of PC. For example, Mohr et al (14) demonstrated that systemic MSC-mediated delivery of soluble tumor necrosis factor-related apoptosis inducing ligand, combined with X-linked inhibitor of apoptosis protein inhibition, could inhibit PC growth and metastasis. Additionally, IL-10-modified human MSCs were shown to inhibit PC progression by suppressing the secretion of pro-inflammatory cytokines IL-6 and TNF-α and inhibiting tumor angiogenesis (15). The role of MSCs in PC is closely associated with their derived EXOs (16).

EXOs are extracellular vesicles (EVs) with a diameter of 30–150 nm that are capable of transmitting complex information between cells (17), across distant tissues (18) and between tumor and stromal compartments (19). They originate from a wide variety of sources and are present in nearly all bodily fluids, and EXOs from different origins exhibit distinct functions (20). MSC-derived EXOs (MSC-EXOs) share numerous functional similarities with MSCs. However, compared with MSCs, MSC-EXOs demonstrate enhanced safety, superior penetrability, improved compatibility and higher stability when interacting with tumor cells (21,22). In recent years, the role of MSC-EXOs in the treatment of PC has been extensively investigated. For instance, it has been reported that human umbilical cord MSC-EXOs (hUC-MSC-EXOs) can promote the growth of pancreatic ductal adenocarcinoma by transferring microRNA (miR/miRNA)-100-5p into the PC tumor model (23). By contrast, Xie et al (24) reported opposing findings, demonstrating that hsa-miRNA-128-3p carried by hUC-MSC-EXOs suppressed the proliferation, invasion and migration of pancreatic ductal adenocarcinoma cells by targeting galectin-3. These findings indicate that MSC-EXOs serve a dual role in PC. The present article systematically elaborates on the dual tumor-promoting and tumor-suppressing mechanisms of MSC-EXOs in PC. It also clarifies the potential factors influencing this duality and provides direction for their application in targeted PC therapy.

The tumor-promoting role of MSC-EXOs in PC has been demonstrated in multiple studies (23,46,47). For instance, B-MSC-EXOs, AD-MSC-EXOs and UC-MSC-EXOs can jointly exert cancer-promoting effects through different mechanisms of action (Fig. 2). The current section will focus on elucidating the specific molecular mechanisms and signaling pathways underlying their pro-tumorigenic effects, including promoting tumor cell proliferation, shaping an immunosuppressive microenvironment and mediating chemotherapy resistance (Table I). By systematically elaborating these mechanisms, the present study aimed to provide researchers with a clear understanding of the tumor-promoting functions of MSC-EXOs in PC and establish a theoretical foundation for developing future exosome-targeted therapeutic strategies.

Although MSC-EXOs can promote the initiation and progression of PC through various mechanisms, current research focuses more on their tumor-suppressive roles. For instance, UC-MSC-EXOs, B-MSC-EXOs, hA-MSC-EXOs, hAF-MSC-EXOs and Dental-MSC-EXOs can jointly exert anti-cancer effects through different mechanisms of action (Fig. 3). In fact, owing to their notable immunomodulatory capabilities and tumor-homing properties, MSC-EXOs exhibit multifaceted functions in tumor suppression: On the one hand, they can directly inhibit the proliferation of PC cells and induce apoptosis; on the other hand, they can indirectly exert antitumor effects by modulating immune responses. Furthermore, due to their high biocompatibility, low immunogenicity and efficient targeted delivery capacity, MSC-EXOs serve as a highly promising drug delivery system and are widely used for loading antitumor agents, thereby further enhancing their value in suppressing PC (Table II) (48,49). Therefore, despite reports indicating that MSC-EXOs may promote the growth and development of PC, their functions in tumor suppression remain more comprehensive and hold greater translational potential.

Over time, genetic engineering has evolved into a pivotal approach for treating various diseases, including hematological disorders, genetic conditions, and cancers (59–61). Particularly in the field of oncology, continuous technological advancements and expanding applications have notably enhanced the efficacy and safety of genetic engineering-based therapies, demonstrating broad prospects for clinical application. MSC-EXOs have garnered considerable attention in the treatment of PC due to their unique biocompatibility, low immunogenicity and targeted delivery capabilities. However, natural EXOs face limitations such as insufficient targeting specificity, limited efficacy of their cargo and rapid clearance, which substantially restrict their clinical translation and therapeutic effectiveness. Consequently, combining them with genetic engineering strategies can markedly enhance their tumor-targeting ability, treatment specificity and immunomodulatory functions in PC.

PC CAFs serve a critical role in the initiation and progression of PC. Targeted reprogramming of CAFs may represent a promising therapeutic strategy for PC. Zhou et al (62) employed a genetic engineering approach to endogenously modify B-MSC-EXOs, enabling surface display of integrin α5 targeting peptides and concomitant overexpression of miR-148a-3p, thereby achieving precise reprogramming of CAFs and providing new insights for clinical translation of this strategy. On the other hand, Buocikova et al (63) genetically engineered EXOs from placental MSCs to express the yeast cytosine deaminase::uracil phosphoribosyltransferase fusion enzyme. In a model of pancreatic ductal adenocarcinoma, this approach demonstrated potent cytotoxicity-reducing effects. Therefore, it offers a promising cell-free therapeutic strategy for PC. Although genetically engineered MSC-EXOs are considered a promising strategy for cancer treatment, their current application in PC remains in its early stages and requires further in-depth research to advance their development. The development of more efficient and safer engineered exosome-based therapeutic strategies remains a notable challenge in the current treatment of PC.

MSC-EXOs exhibit a dual role in PC, a phenomenon that warrants in-depth consideration. The underlying mechanisms are likely closely associated with the following factors. Firstly, the functional properties of EXOs are notably influenced by their cellular origin. Although EXOs derived from different sources of MSCs share common characteristics, such as high self-renewal capacity, multipotent differentiation potential, immunomodulatory activity, pro-angiogenic effects and tumor-homing ability (64–74) (Fig. 4), the specific molecules present on their surface and their cargo compositions may vary considerably, potentially leading to distinct functional orientations (75–79) (Table III). MSC-EXOs from different tissue sources have demonstrated a dual role in PC, which has been discussed in the present review. On the other hand, the stage of PC progression may also affect the functional outcomes of EXOs. For instance, early-stage PC may respond more favorably to therapy with MSC-EXOs compared with advanced-stage disease; however, this hypothesis still lacks robust experimental evidence and thus represents a critical question that urgently requires validation in future research. In addition, the differences in experimental design within this research field are another reason for the contradictions among different research results. Specifically, the differences in the extraction and identification methods of EXOs, cell co-culture systems and animal models (such as mouse strains, quantities and tumor-bearing sites) may all introduce notable heterogeneity, thereby affecting the comparability and repeatability of research conclusions.

In summary, MSC-EXOs exhibit a notable dual role in PC. The present review has systematically discussed their specific molecular mechanisms and functional characteristics in PC, and summarized the latest research advances in engineered modification of MSC-EXOs. In-depth elucidation of the key molecules, proteins and signaling pathways involved will provide new research directions and intervention strategies for the treatment of PC.

Despite the considerable tumor-suppressive potential of MSC-EXOs in PC, several unresolved issues and challenges remain. First, the techniques for isolating and extracting MSC-EXOs are still inadequate. Although multiple methods have been developed for exosome isolation and extraction, such as ultracentrifugation (80,81), ultrafiltration (82–84), flushing separation (85), precipitation (86–88), immunoaffinity capture (89–91), microfluidics (92–95) and mass spectrometry (96), each of these approaches has its own limitations. There is currently a lack of a simple, efficient, cost-effective and standardized extraction protocol suitable for clinical application. Second, research on and preparation of MSC-EXOs lack unified standards. No authoritative institutions have yet established clear guidelines for their isolation, preparation, characterization and functional evaluation. Third, large-scale production, storage and transportation systems remain underdeveloped. Systematic research and solutions are still needed regarding large-scale preparation, long-term stable storage methods and potential loss of activity and integrity during transportation. Fourth, evidence for clinical translation is insufficient. Most current studies are limited to animal experiments; future research should focus on clinical trials to validate the safety and efficacy of these EXOs in human applications. Fifth, the immunogenicity risks brought about by the engineering modification of MSC-EXOs need to be systematically evaluated. For example, whether the natural low immunogenicity advantage of MSC-EXOs will be altered after engineering. Or, whether it may trigger an immune response in the body, especially in the context of repeated administration for PC, which would be a core issue regarding treatment safety. Sixth, the dense fibrotic matrix of PC may severely impede the penetration ability of EXOs, and their pharmacokinetic performance in this environment requires further research and confirmation. Finally, there is a lack of horizontal efficacy comparisons among various treatment methods for PC. For instance, compared with traditional nanoparticles (such as liposomes) that have entered clinical application, MSC-EXOs may have inherent advantages in active targeting and biocompatibility, but they are slightly inferior in drug loading capacity and the maturity of production processes (97). However, future research should prospectively explore strategies for combining the two to achieve synergistic therapeutic effects.

Although the present article systematically expounds the research progress of MSC-EXOs in PC, there are still certain limitations. Firstly, due to the rapid development of research in this field, this article may not be able to cover all the latest released research achievements. Secondly, the discussion on the mechanism of MSC-EXOs in promoting cancer still needs to be further clarified. In addition, the analysis of the potential and challenges of EXOs derived from engineered MSCs in this field needs to be strengthened. Looking to the future, first of all, researchers should focus on developing a simple, efficient and low-cost standardized extraction scheme for the separation and extraction of EXOs. Secondly, more in-depth exploration and research should be performed on the role of MSC-EXOs in PC to address the potential loss issues that may arise during their large-scale production, storage and transportation. In addition, a systematic safety assessment of the immunogenicity risk and in vivo pharmacokinetic behavior of engineered modified EXOs is necessary, which is a prerequisite for their clinical transformation. Another important task lies in performing a horizontal efficacy comparison between exosome therapy and other treatment methods, with the aim of providing the optimal treatment strategy for patients with PC. Finally, accelerating the transformation of MSC-EXOs from basic research to clinical practice makes it possible for them to become an important component of the comprehensive treatment system for PC.

MSC-EXOs serve as highly plastic messengers in PC, where their role in promoting or suppressing tumor progression is not fixed but rather determined by their specific surface molecules and cargo contents, which are closely associated with the diverse origins of MSCs. Future research should focus on transforming MSC-EXOs from a ‘double-edged sword’ into a precise weapon against PC. The primary task is to deeply explore its specific active ingredients and their precise regulatory mechanisms in PC and, on this basis, strategies for engineering and modifying MSC-EXOs should be established. At the same time, establishing standardized, repeatable, low-cost yet high-purity separation and purification technologies is the core step for it to move towards clinical application. In addition, it is important to actively explore the combined application of EXOs therapy and existing treatment methods. Only through in-depth exploration at multiple levels can this promising treatment method be advanced from the laboratory to clinical practice, bringing new treatment options for patients with PC.