Mesenchymal stem cells (MSCs) have gained significant attention in regenerative medicine due to their multipotency, immunomodulatory properties, and notably, their intrinsic ability to migrate toward sites of injury and inflammation. Importantly, this tumor-homing ability has been well-documented and is now being leveraged as a key strategy in targeted cancer therapy.
Tumor-Homing Mechanism of MSCs
Tumor tissues are known to produce a range of inflammatory mediators, including chemokines, cytokines, and growth factors such as SDF-1 (CXCL12), TGF-β, and VEGF.
These factors act as chemical attractants, guiding MSCs via receptor–ligand interactions.
- CXCL12–CXCR4 Axis
This is one of the most thoroughly studied mechanisms. CXCL12 secreted by tumor cells binds to CXCR4 receptors on MSCs, guiding their migration toward tumors. - Transendothelial Migration
Once near the tumor, MSCs extravasate through the vascular endothelium. This process is mediated by molecules such as integrins, selectins, and matrix metalloproteinases (MMPs).
Exosomes: MSCs’ Tumor-Homing Message Carriers
Recent studies have confirmed that this tumor-homing capacity is not limited to MSCs, but also retained in the exosomes they secrete.
- General Characteristics of MSC-Exosome
MSC-derived exosomes are 30–150 nm extracellular vesicles that carry miRNAs, mRNAs, proteins, and lipids. They reflect the molecular and functional traits of their parent cells. - Surface Molecules for Targeting
Exosomes derived from MSCs express specific integrins and tetraspanins that mediate tissue tropism and selective organ adhesion. Recent studies (Hoshino et al., 2024) have shown that exosomal integrin α6, β4, and β1 are enriched in lung-tropic exosomes, while β5 and αv are associated with liver tropism, underscoring the crucial role of integrin patterns in directing exosome biodistribution
Moreover, miRNA‑3940‑5p carried by MSC-derived exosomes directly targets integrin α6 (ITGA6) in colorectal cancer (CRC) cells, inhibiting epithelial‑mesenchymal transition (EMT), invasion, and metastasis in vivo. These findings reinforce how exosomal integrins not only dictate physical homing but also functional targeting via downstream signaling modulation. - Experimental Evidence of Tumor Targeting
Several in vivo tracking studies confirm preferential tumor accumulation of MSC-derived exosomes in murine models. Bioluminescent exosomes from Renilla luciferase‑expressing MSCs accumulated in Lewis lung carcinoma (LLC) tumors and induced apoptosis by downregulating p‑ERK and upregulating cleaved caspase‑3/PARP, demonstrating both tumor-homing and therapeutic effects.
Another study used gold nanoparticle (GNP)‑labeled MSC exosomes and CT imaging in A431 tumor‑bearing mice, revealing significantly higher tumor accumulation and deeper intratumor penetration of MSC‑exo compared to tumor cell-derived exosomes. Non-encapsulated GNPs remained at tumor peripheries, whereas MSC‑exo penetrated into tumor cytoplasm.
These quantitative imaging studies underscore not only the biodistribution preferences of MSC‑derived exosomes, but also their superior tumor access and therapeutic payload delivery compared to alternative vesicle types.
Functional Differences Based on Exosome Origin
- Cancer Cell–Derived Exosomes
These often contain pro-tumorigenic miRNAs such as miR-21 and miR-155, promoting metastasis, angiogenesis, and chemoresistance. - MSC-Derived or Engineered Exosomes
Exosomes from healthy or engineered MSCs carry tumor-suppressive miRNAs like miR-16, let-7, and miR-34a, and have shown anti-cancer effects such as inducing apoptosis and inhibiting proliferation in various models.
Immune Modulation via Exosomes
Exosomes act not only as carriers of molecular cargo but also as crucial mediators that influence the immune system. Particularly, MSC-derived exosomes can modulate the tumor microenvironment (TME) by affecting immune cell behavior.
- Immunosuppression by Tumor-Derived Exosomes
- Cancer cell–derived exosomes often carry immunosuppressive molecules such as TGF-β, IL-10, and PD-L1, which inhibit the function of immune cells including T cells, natural killer (NK) cells, and macrophages. These exosomes contribute to tumor immune evasion and may interfere with the efficacy of immune checkpoint inhibitors. For instance, Haderk et al. (2017) demonstrated that tumor-derived exosomes impair dendritic cell function and reduce T cell activation, promoting immune tolerance in the tumor microenvironment.
- Immune Activation by Engineered Exosomes
Conversely, engineered exosomes, including those derived from MSCs, can be loaded with immune-activating molecules such as IL-12, IFN-γ, or tumor antigen peptides to enhance anti-tumor immune responses. Recent preclinical studies have shown that such exosomes promote cytotoxic T cell responses and inhibit tumor growth, breaking immune tolerance. Additionally, exosome-based antigen delivery is being explored in cancer vaccine development and combined immunotherapy strategies.
Strategies for Therapeutic Engineering
To maximize the therapeutic efficacy of MSC-derived exosomes, various engineering approaches have been developed focusing on improving targeting specificity and cargo delivery.
- Genetic Engineering of MSCs
MSCs can be genetically modified to overexpress therapeutic miRNAs, siRNAs, or proteins (e.g., TRAIL, p53, IFN-β), which are subsequently incorporated into secreted exosomes. Kamerkar et al. (2017) reported that MSC-derived exosomes loaded with KRAS^G12D siRNA significantly inhibited tumor growth and improved survival in a pancreatic cancer model, demonstrating effective gene silencing delivery. Other miRNAs such as miR-146b, miR-122, and miR-199a-3p have been successfully delivered via engineered MSC exosomes to suppress glioma and hepatocellular carcinoma in preclinical models. - Surface Functionalization of Exosomes
Exosome surfaces can be functionalized with targeting ligands, such as RGD, iRGD peptides, or antibodies against tumor-specific receptors like EGFR or HER2, to enhance tumor targeting. This strategy increases binding affinity to cancer cells, facilitating better tumor penetration and accumulation. Chemical modifications like PEGylation are also employed to improve exosome stability and immune evasion in vivo. - Drug Loading and Combination Therapies
Exosomes can be loaded with chemotherapeutic agents (e.g., paclitaxel, doxorubicin) or immunomodulatory molecules to deliver drugs selectively to tumor cells. This approach reduces systemic toxicity and enhances the therapeutic index, enabling combined modality treatment
Table1. Preclinical Studies of MSC-Derived Exosomes in Cancer Therapy
| Loaded Cargo | Target Cancer | Main Therapeutic Effect | Experimental Model | Study Title / Source |
| miR‑122 | Hepatocellular carcinoma (HCC) | Enhanced chemosensitivity to sorafenib | In vitro, In vivo (mouse) | Exosomes derived from miR‑122 modified adipose tissue MSCs increase chemosensitivity of HCC (Lou et al., 2015) |
| miR‑146b | Glioma | Tumor growth inhibition | In vivo (rat) | Exosomes from MSCs expressing miR‑146b inhibit glioma growth (Katakowski et al., 2013) |
| KRAS^G12D siRNA | Pancreatic cancer (PDAC) | Tumor suppression, increased survival | In vivo (mouse) | Exosomes Facilitate Therapeutic Targeting of Oncogenic KRAS in Pancreatic Cancer (Kamerkar et al., 2017) |
| Paclitaxel | Lung, breast cancer | Drug delivery, apoptosis | In vitro, In vivo | Paclitaxel-loaded exosomes from MSCs for targeted cancer therapy (Pharmaceutics, 2021) |
| TRAIL protein | Lung, breast, neuroblastoma | Tumor cell apoptosis | In vitro, In vivo | Engineered MSC-derived exosomes with TRAIL for cancer therapy (IJMS, 2024) |
| S3I‑201 (STAT3 inhibitor) | Triple-negative breast cancer | STAT3 inhibition, apoptosis | In vitro, In vivo | Exosomes from Wharton’s Jelly MSCs deliver STAT3 inhibitor to TNBC (Cells, 2023) |
| miR‑199a-3p | Hepatocellular carcinoma | mTOR pathway inhibition, suppressed proliferation | In vitro, In vivo | MSC-derived exosomal miR-199a-3p inhibits HCC growth (Mol Cancer, 2017) |
| Doxorubicin + MUC1 aptamer | Colorectal cancer | Targeted delivery, reduced toxicity | In vitro, In vivo | Doxorubicin-loaded, MUC1-aptamer-functionalized exosomes for CRC therapy (Nanoscale, 2020) |
Challenges and Considerations for Clinical Translation
The biological effects of MSC-derived exosomes are significantly influenced by the origin of MSCs, culture conditions, and the molecular composition of the exosomes. Therefore, for successful clinical translation, it is essential to establish rigorous characterization, ensure reproducibility, and standardize the processes of exosome production and purification.
Conclusion
The tumor-homing capacity of MSCs, combined with the natural delivery and targeting potential of their exosomes, represents a scientifically validated strategy in precision oncology. By tailoring the origin of MSCs and engineering their exosomal cargo, researchers can develop effective, biocompatible, and low-toxicity anti-cancer treatments. Given their advantages in immunogenicity, biocompatibility, and tumor targeting, MSC-derived exosomes hold strong promise as the next generation of cell-free cancer therapeutics.
References
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