Search Strategy

A comprehensive literature search was performed using PubMed and Web of Science databases to identify pertinent studies. The search strategy employed a combination of terms related to “exosomes”, “stem cells”, and “oral cancer”. An English language restriction was applied, and articles published before 1 March 2024 were included in the search.

Study Selection

The search aimed to identify pertinent research that explores the therapeutic potential of stem cell-derived exosomes in oral cancer.

Inclusion and Exclusion Criteria

This review included original research articles, clinical trials, studies, and animal model studies that investigated stem cell-derived exosomes as a potential therapeutic approach for oral cancer. Only studies published in English were included.

Studies were excluded if they did not focus specifically on oral cancer. Additionally, studies that did not involve stem cell-derived exosomes or focused on non-exosomal approaches were excluded. Reviews, meta-analyses, and conference abstracts were excluded due to a lack of original data.

The EndNote citation software was utilised to conduct a three-phase examination process on the articles acquired from the databases. Duplicate files were removed in Phase I. Phase II involved analysing the titles and abstracts. Phase III involved a thorough examination of articles from the selected abstracts. Two reviewers, MAM and WNS, conducted separate evaluations of the titles and abstracts of all identified studies. To ensure consistency and minimise bias, the reviewers adhered to a predefined process for article selection and data extraction, which included detailed discussions to resolve any discrepancies. Any disagreements were resolved through consultation with a third reviewer (RM).

Data Extraction and Analysis

For each study included, we utilised a structured data extraction process to gather relevant information, including the location, publication year, exosome origin, exosomal cargo, target cell (for studies), and animal species and sample size (for studies), pathway involved, and primary outcome. The reviewers jointly reviewed the extracted data to ensure accuracy and consistency in interpretation, thereby reducing variability. This review presents its findings through a narrative synthesis methodology adhering to the PRISMA-ScR guidelines20. Additionally, no quality assessment was performed, as scoping reviews aim to inclusively identify all accessible evidence and underscore their primary attributes, irrespective of their quality. Figure 1 illustrates the literature search process.

Summary of Evidence

Our objective was to assess the therapeutic potential of stem cell-derived exosomes in the treatment of oral cancer through a comprehensive evaluation. The most significant findings were as follows: Exosomes derived from stem cells identified as potential therapeutic agents include UC-MSCs, hiTDEs, SHED-Exo, MenSCs, CAF exosomes, and hBMSCs. These exosomes demonstrate multifaceted effects, including the reduction of pro-inflammatory cytokines, which are known to fuel tumor growth and progression30. Furthermore, they play a crucial role in inducing apoptosis, a process vital for eliminating cancerous cells22, 24. Moreover, stem cell-derived exosomes have been shown to down-regulate HOX transcript antisense intergenic RNA (HOTAIR), an oncogenic long non-coding RNA associated with aggressive tumor behavior in oral cancer21. On the other hand, CSC_EVs play a crucial role in reshaping the tumor microenvironment (TME) by potentially inducing the transformation of normal gingival fibroblasts (NGFs) into cancer-associated fibroblasts (CAFs), thereby promoting their metastatic potential. Simultaneously, cancer stem cells contribute significantly to the progression of oral cancer by altering the TME23, 31, 32. Through the secretion of CSC_EVs, these cells enhance self-renewal, metastasis, and resistance to cisplatin in cancer cells. Additionally, CSC_EVs actively stimulate endothelial cell survival, migration, and invasion, crucial processes for tumor development, sustenance, and angiogenesis23, 33. However, the addition of specific treatments has been shown to inhibit angiogenesis by exosomes, which is essential for tumor growth and metastasis23.

Therapeutic Potential of Stem Cell-Derived Exosomes in Oral Cancer

EVs are lipid bilayer vesicles that cells constantly release into the extracellular environment. EVs consist of three different types: exosomes, microvesicles, and apoptotic bodies34, 35. The molecules carried by these EVs include RNAs, miRNAs, proteins, DNA fragments, and noncoding RNAs, which are commonly carried within EVs as cargo and could potentially function as therapeutic and diagnostic biomarkers for OSCC36, 37. The biological effects of exosomes on recipient cells are influenced by their cell of origin, which also affects their composition and ability to target cells. MSCs generate exosomes that interact with different types of cells, affecting their biological properties and possibly controlling disease progression and maintaining physiological homeostasis, in contrast to exosomes produced from human epidermal carcinoma cells (A431-exo)38. MSC-derived exosomes exhibited greater tumor accumulation, penetration, and distribution within tumor tissues in an animal model of head and neck cancer39. These results imply that exosomes produced from MSCs may have greater potential for targeted tumor therapy.

The promising role of stem cell-derived exosomes in oral cancer therapy is underscored by their ability to down-regulate pro-inflammatory cytokines, induce apoptosis, and inhibit oncogenic processes40. When compared to other emerging cancer therapies, such as targeted therapies (including immune checkpoint inhibitors, small-molecule inhibitors, monoclonal antibodies, and CAR-T cell therapy), exosome-based therapies offer several potential advantages41. While these conventional treatments are highly effective for specific cancers, including oral cancer, they can present challenges such as high costs, complex administration, and immune-related adverse events. In contrast, exosomes are naturally derived, with low immunogenicity and excellent biocompatibility, enabling them to deliver therapeutic molecules directly to tumor cells42. These distinct characteristics position exosomes as a promising treatment strategy with the potential to overcome some limitations of conventional therapies43. Furthermore, exosome-based therapies can modulate gene expression and cellular signaling without permanently altering DNA, providing a safer and more controlled intervention16.

Exosomes released by stem cells demonstrate the ability to inhibit tumor growth, invasion, and migration, as well as trigger programmed cell death44. A study conducted by Abdelwhab . in 2023 demonstrated that treatment with UC-MSCs-exos exerted a suppressive effect on OSCC cell lines, indicating a potential therapeutic role. Notably, UC-MSCs-exos treatment led to a substantial decline in the levels of IL-6 and TNF-alpha, with the extent of reduction depending on the dosage21. IL-6 and TNF-alpha are recognized for their pivotal involvement in numerous tumorigenic mechanisms, including angiogenesis and sustaining proliferative signaling in solid cancers45. Dysregulation of IL-6 signaling has been implicated in promoting cancer cell proliferation and survival46. Furthermore, the role of HOTAIR has been recognized as a tumor suppressor in head and neck tumors through its function as a molecular sponge for miR-148a47. UC-MSCs-exos have an inhibitory effect on the expression of HOTAIR in OSCC cells, leading to the inhibition of cell proliferation and tumor development21. Another study conducted by Rosenberger . in 2019 demonstrated that treating endothelial cells with MenSCs and UC-MSCs resulted in increased cytotoxicity, decreased secretion of vascular endothelial growth factor (VEGF), and inhibited the formation of new blood vessels both and 26. The included studies showcased the therapeutic potential of exosomes derived from various stem cells, as outlined in Table 3. The proposed model for the therapeutic utilization of exosomes derived from stem cells could be utilized to facilitate anti-proliferative effects in anticancer treatment, as depicted in Figure 2.

A significant challenge in oral cancer management is chemoresistance48, 49. Cancer stem cells (CSCs), a small subpopulation of tumor cells distinguished by specific markers, are implicated in disease progression and treatment resistance in various cancers. CSC-derived small extracellular vesicles (sEVs) are particularly responsible for promoting tumor growth and therapy resistance49, 50. These CSCs secrete sEVs that contribute to an immunosuppressive tumor microenvironment and facilitate M2 macrophage polarization, as observed in glioblastoma and colon cancer51, 52. M2 tumor-associated macrophages (M2-TAMs) are among the most abundant immunosuppressive cell types in the tumor microenvironment53. Additionally, CSCs exhibit characteristics such as enhanced self-renewal, drug efflux, promotion of epithelial-mesenchymal transition (EMT), and secretion of oncogenic factors, remodeling the tumor microenvironment to promote cancer progression54. Therefore, targeting CSCs has become a priority in OSCC management.

A study conducted by Chen in 2019 reported that CSC_EVs enhance the development of resistance to CDDP, the ability to form colonies, and the formation of tumor spheres in OSCC cells. The bioinformatics research indicated that EVs derived from OSCC_EVs contain a high concentration of microRNA (miR)-21-5p. This specific microRNA is linked to enhanced metastasis, stem cell-like properties, resistance to chemotherapy, and poor prognosis in patients23. Moreover, CSC_EVs induced a CAF phenotype in NGFs, which in turn enhanced the oncogenic properties of OSCC cells55. Treatment with OV, a bioactive compound from , successfully inhibited the development of OSCC and decreased the cargo content in CSC_EVs. This inhibition disrupted the interaction between EVs and the TME, leading to a reduction in self-renewal and transformation of normal fibroblasts into cancer-associated fibroblasts (NGF-CAF)23. The results provide compelling evidence that, despite CSCs promoting oral cancer progression and chemoresistance, treatment with OV decreased the oncogenic content of EV cargos in both OSCC cells and CSCs.

A study conducted by Wu in 2022 highlighted the pivotal role of OSCC-CSC-derived exosomes in modulating the tumor microenvironment. These exosomes transfer UCA1, a long non-coding RNA, which targets LAMC2 to promote M2 macrophage polarization25. This polarization significantly contributes to immunosuppression by inhibiting CD4 T-cell proliferation and IFN-γ production and . Moreover, M2-TAMs influenced by exosomal UCA1 enhance OSCC cell migration, invasion, and tumorigenicity25, 56. LAMC2, a laminin gamma 2 chain, is known to drive aggressive cancer behavior through interactions with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and has been associated with macrophage infiltration in lung cancer57, 58. It also mediates chemotherapy sensitivity in ovarian cancer via exosomal miR-146a and the PI3K/AKT pathway59. These findings reveal that LAMC2 facilitates the effects of OSCC-CSC-derived exosomal UCA1, promoting M2 macrophage polarization through the PI3K/AKT pathway and further emphasizing its central role in OSCC progression.

Therapeutic agents like proteins, RNAs, miRNAs, small interfering RNAs (siRNAs), and targeted drugs have been integrated with exosomes to improve bioactivity and facilitate targeted drug delivery60. This integration is achieved through methods such as electroporation, ultrasonication, parental cell alteration, or direct incubation61. Following the integration of therapeutic agents into exosomes, they are able to penetrate the targeted recipient cell, facilitating the subsequent release of the intended cargo. The most common cargo is miRNAs, which are of great interest owing to their essential role in post-transcriptional gene regulation62. A recent study by Liu . (2022) demonstrated that SHED-Exos are enriched with miR-100-5p and miR-1246, which are transferred to endothelial cells, leading to a reduction in tube formation through the downregulation of vascular endothelial growth factor A (VEGFA) expression. VEGFA plays a critical role in tumor angiogenesis, growth, and metastasis, highlighting the potential of SHED-Exos as a novel therapeutic strategy for anti-angiogenic treatment, as evidenced by their ability to inhibit angiogenesis both and 24. In contrast, a more recent study observed that SHED-Exo aggregates promoted angiogenesis, which contrasts with the findings of Liu (2022). The study showed that OSCC-released miR-1825 was efficiently transferred to endothelial cells via exosomes, contributing to angiogenesis22. Moreover, miR-1825 in endothelial cells was found to promote angiogenesis by disrupting the TSC2/mTOR axis, which is known to be involved in angiogenic processes63. The TSC/mTOR axis in endothelial cells is essential for vasculature and embryogenesis, with cancer-related kinases modulating mTOR activity by inactivating the TSC complex64, 63. TSC2, an upstream negative regulator of mTOR, plays a key role in regulating processes such as cell proliferation and angiogenesis and is often dysregulated in various cancers65. Additionally, mTOR is involved in the early response to hypoxia, inducing endothelial cell proliferation primarily through Akt signaling22. These contrasting findings underscore the paradoxical role of exosomes in angiogenesis, where they can either suppress or promote angiogenesis depending on the tumor microenvironment. In addition to those highlighted in this review, additional miRNAs such as miR-1825, miR-21-5p, miR-100-5p, miR-1246, and miR-101-3p may hold substantial implications in oral cancer. The precise functions and contributions of these miRNAs might be elucidated in forthcoming studies.

Limitations of Included Studies

Cell lines used for oral cancer research are essential for discovering potential therapeutic targets; however, their responses may differ from those of cells within an organism66. While studies provide valuable insights into the underlying mechanisms, methodological differences such as variations in exosomal molecular cargo, donor cell types, and cell culture conditions may limit the generalizability of the results. Out of the nine studies reviewed, six included components, which are more reflective of real-world scenarios, but these studies also exhibited varying animal species and small sample sizes, with one study failing to report its sample size23. Furthermore, none of the studies provided long-term follow-up data, and none specified the histological grade of oral cancer, both of which may have influenced the outcomes. Regarding the role of MSC-derived exosomes in angiogenesis, one study reported that MSC-derived exosomes enhance angiogenesis22, while other studies suggested that they inhibit blood vessel formation24, 26. To validate the specificity of these exosomes, well-controlled studies with standardized methodologies and longer follow-up periods are needed to confirm the findings, as this would significantly enhance the clinical applications of stem cell-derived exosomes in oral cancer treatment.

Limitations of This Study

Some potentially pertinent studies may have been overlooked owing to their absence from the indexed databases utilized in the search process. The quality of the studies was not assessed in this review, in accordance with the fundamental characteristics of reviews.

Future Perspectives

Advanced studies on exosomes in oral cancer are crucial for elucidating their roles in chemotherapy resistance, tumor phenotypic alteration, immunological control, angiogenesis, and metastasis. Despite progress, several questions remain unanswered and warrant further exploration. Exosomes represent a promising frontier in drug delivery owing to their low immunogenicity and superior biocompatibility, offering potential applications in diagnosis and prognosis67. As indicated by our included studies, stem cell-derived exosomes unravel the therapeutic potential for oral cancer.

To advance this research, it will be essential to explore the molecular mechanisms that govern exosome-mediated communication between cancer cells and the tumor microenvironment. This can include investigating the role of exosome cargo, such as specific proteins, DNAs, RNAs, miRNAs, and lipids, in promoting or inhibiting tumor progression68. Additionally, future studies should investigate the modulation of exosome release in response to different environmental stimuli, such as hypoxia or drug treatment, to better understand how these factors influence their therapeutic potential.

Furthermore, our findings provide a foundation for future research using , , and preclinical trials to evaluate the effectiveness of treatments for oral cancer. In forthcoming research, it will be imperative to evaluate the efficacy of exosomes in a metastatic disease model. To achieve this, it is crucial for exosomes to specifically target tumor sites in the body after being administered systemically. Previous research has demonstrated that exosomes released by different types of cells are capable of reaching tumors. Nonetheless, different exosome subtypes may exhibit distinct innate homing capabilities . Hence, conducting focused studies on stem cell-derived exosomes is crucial for evaluating their biodistribution and tumor-homing characteristics14. In clinical applications, it will be critical to assess the safety and toxicity profile of exosome-based therapies. Well-designed phase I and II clinical trials that evaluate the pharmacokinetics, biodistribution, and immune response to exosomes will be essential in confirming their clinical feasibility. Long-term follow-up studies will be needed to assess the sustained efficacy and potential adverse effects of exosome-based treatments, particularly in patients with advanced-stage or metastatic oral cancer.

Finally, investigating the potential for combination therapies, where exosomes are used alongside conventional chemotherapy, immunotherapy, or targeted therapies, could provide synergistic benefits. This approach could enhance the overall treatment response, reduce resistance, and improve patient outcomes. By incorporating these research directions into future studies, we can better define the clinical applications of stem cell-derived exosomes in oral cancer treatment and significantly enhance their therapeutic potential.