Progress and challenges of mesenchymal stem cells as oncolytic virus delivery systems: A bibliometric analysis of the top 100 most-cited papers in the past ten years

Abstract

Oncolytic virotherapy has emerged as a promising approach to cancer treatment, and mesenchymal stem cells (MSCs) are increasingly recognized as effective carriers to enhance the delivery and efficacy of oncolytic viruses (OVs). This study explores the potential use of MSCs as carriers for OVs in targeted cancer therapy. MSCs are considered ideal delivery vehicles for OVs due to their immunomodulatory properties, inherent tumor-homing ability, and capacity to protect and transport therapeutic agents. Advances in genetic engineering have enhanced the interaction between MSCs and OVs, improving delivery efficiency and therapeutic outcomes in cancer treatment. This study conducted a bibliometric analysis of the 100 most-cited articles on both MSCs and OVs, using data from the Web of Science Core Collection database. It identified major trends, challenges, and research hotspots, highlighting significant progress in preclinical studies while noting ongoing issues related to delivery efficiency, virus modification, and tumor microenvironment optimization. The findings underscore the promise of MSCs as effective delivery systems for Ovs and outline emerging research areas, such as precise delivery methods and clinical applications, alongside current obstacles. As this field advances, it is expected to play a crucial role in the future of cancer immunotherapy.

Keywords

Mesenchymal stem cells / Oncolytic viruses / Drug delivery systems / Cancer immunotherapy / Bibliometric analysis

References

[1] Khanmohammadi S, Fallahtafti P, Rezaei N. Introduction to Stem Cells and Immunity. In: Rezaei N, ed. Comprehensive Hematology and Stem Cell Research. 1st ed. Oxford: Elsevier; 2024:1-25.

[2] Pharoun J, Berro J, Sobh J, et al. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur J Pharmacol. 2024; 977:176719. doi: 10.1016/j.ejphar.2024.176719

[3] Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8(4):315-317. doi: 10.1080/14653240600855905

[4] Han Y, Li X, Zhang Y, et al. Mesenchymal Stem Cells for Regenerative Medicine. Cells. 2019; 8(8):886. doi: 10.3390/cells8080886

[5] Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med. 2001; 7(6):259-264. doi: 10.1016/s1471-4914(01)02016-0

[6] Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284(5411):143-147. doi: 10.1126/science.284.5411.143

[7] Amadeo F, Trivino Cepeda K, Littlewood J, et al. Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action? Emerg Top Life Sci. 2021; 5(4):549-562. doi: 10.1042/ETLS20200334

[8] Han X, Liao R, Li X, et al. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Signal Transduct Target Ther. 2025; 10(1):262. doi: 10.1038/s41392-025-02496-1

[9] Jasim SA, Yumashev AV, Abdelbasset WK, et al. Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune diseases. Stem Cell Res Ther. 2022; 13(1):101. doi: 10.1186/s13287-022-02782-7

[10] Zeng L, Liu C, Wu Y, et al. Efficacy and safety of mesenchymal stromal cell transplantation in the treatment of autoimmune and rheumatic immune diseases: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther. 2025; 16(1):65. doi: 10.1186/s13287-025-03997-w

[11] Lalu MM, Mazzarello S, Zlepnig J, et al. Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Transl Med. 2018; 7(12):857-866. doi: 10.1002/sctm.18-0120

[12] Yu M, Ma H, Lai X, et al. Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases. Front Aging Neurosci. 2025; 17:1592578. doi: 10.3389/fnagi.2025.1592578

[13] Xie X, Song Q, Dai C, et al. Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease: a phase I/II clinical trial. Gen Psychiatr. 2023; 36(5):e101143. doi: 10.1136/gpsych-2023-101143

[14] Stewart CA, Daniel S, Curvino EJ, et al. mRNA engineering of allogeneic mesenchymal stem cells enables coordinated delivery of T cell engagers and immunotherapeutic cues. Nat Biomed Eng. 2025. doi: 10.1038/s41551-025-01433-5

[15] Zhang H, Feng Y, Xie X, et al. Engineered Mesenchymal Stem Cells as a Biotherapy Platform for Targeted Photodynamic Immunotherapy of Breast Cancer. Adv Healthc Mater. 2022; 11(6):e2101375. doi: 10.1002/adhm.202101375

[16] Niess H, Thomas MN, Schiergens TS, et al. Genetic engineering of mesenchymal stromal cells for cancer therapy: turning partners in crime into Trojan horses. Innov Surg Sci. 2016; 1(1):19-32. doi: 10.1515/iss-2016-0002

[17] Ramirez M, Ruano D, Moreno L, et al. First-in-child trial of celyvir (autologous mesenchymal stem cells carrying the oncolytic virus ICOVIR-5) in patients with relapsed and refractory pediatric solid tumors. J Clin Oncol. 2018; 36(15_suppl):10543. doi: 10.1200/JCO.2018.36.15_suppl.10543

[18] Yoon AR, Rivera-Cruz C, Gimble JM, Yun CO, Figueiredo ML. Immunotherapy by mesenchymal stromal cell delivery of oncolytic viruses for treating metastatic tumors. Mol Ther Oncolytics. 2022; 25:78-97. doi: 10.1016/j.omto.2022.03.006

[19] Aljabali AAA, Bashatwah R, Gammoh O. The dual promise of oncolytic viruses: selective targeting and therapeutic enhancement in cancer treatment. Explor Immunol. 2025; 5:1003204. doi: 10.37349/ei.2025.1003204

[20] He X, Yao W, Zhu JD, et al. Potent antitumor efficacy of human dental pulp stem cells armed with YSCH-01 oncolytic adenovirus. J Transl Med. 2023; 21(1):688. doi: 10.1186/s12967-023-04554-w

[21] Ozcan AI, Aquino Lomicronpez A, Wolff AN, et al. Mesenchymal stromal cells protect combined oncolytic and helper-dependent adenoviruses from humoral immunity. Mol Ther Methods Clin Dev. 2024; 32(3):101279. doi: 10.1016/j.omtm.2024.101279

[22] Shi Y, Zhang J, Li Y, et al. Engineered mesenchymal stem/stromal cells against cancer. Cell Death Dis. 2025; 16(1):113. doi: 10.1038/s41419-025-07427-y

[23] Atiya H, Frisbie L, Pressimone C, Coffman L. Mesenchymal Stem Cells in the Tumor Microenvironment. In: Birbrair A, ed. Tumor Microenvironment: Non-Hematopoietic Cells. Cham: Springer; 2020:31-42. doi:10.1007/978-3-030-37184-5_3

[24] Afkhami H, Mahmoudvand G, Fakouri A, et al. New insights in application of mesenchymal stem cells therapy in tumor microenvironment: pros and cons. Front Cell Dev Biol. 2023; 11:1154208. doi: 10.3389/fcell.2023.1154208

[25] Yoon AR, Hong J, Li Y, et al. Mesenchymal Stem Cell-Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma. Cancer Res. 2019; 79(17):4503-4514. doi: 10.1158/0008-5472.CAN-18-3900

[26] Choy EY, Leong CO, Cheong SK, Then KL, Then KY. Adeno-Associated Virus-Engineered Umbilical Cord-Derived Mesenchymal Stromal Cells Overexpressing Human sFlt-1 for Anti-Angiogenesis. Life. 2025; 15(5):709. doi: 10.3390/life15050709

[27] Kalluri VS, Smaglo BG, Mahadevan KK, et al. Engineered exosomes with Kras(G12D) specific siRNA in pancreatic cancer: a phase I study with immunological correlates. Nat Commun. 2025; 16(1):8696. doi: 10.1038/s41467-025-63978-y

[28] Davies A, Sage B, Kolluri K, et al. TACTICAL: A phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma. J Clin Oncol. 2019; 37(15_suppl):TPS9116. doi: 10.1200/JCO.2019.37.15_suppl.TPS9116

[29] Chen C. CiteSpace: A Practical Guide for Mapping Scientific Literature. New York, N.Y: Nova Science Publishers; 2016.

[30] van Eck NJ, Waltman L. Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics. 2010; 84(2):523-538. doi: 10.1007/s11192-009-0146-3

[31] Aria M, Cuccurullo C. bibliometrix: An R-tool for comprehensive science mapping analysis. J Informetr. 2017; 11:959-975. doi: 10.1016/j.joi.2017.08.007

[32] Mozaffari Nejad AS, Noor T, Munim ZH, Alikhani MY, Ghaemi A. A bibliometric review of oncolytic virus research as a novel approach for cancer therapy. Virol J. 2021; 18(1):98. doi: 10.1186/s12985-021-01567-3

[33] Hezam K, Fu E, Zhang J, Li Z. Therapeutic trends of priming mesenchymal stem cells: A bibliometric analysis. Biochem Biophys Rep. 2024; 38:101708. doi: 10.1016/j.bbrep.2024.101708

[34] Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012; 30(7):658-670. doi: 10.1038/nbt.2287

[35] Sonabend AM, Ulasov IV, Tyler MA, et al. Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells. 2008; 26(3):831-841. doi: 10.1634/stemcells.2007-0758

[36] Yong RL, Shinojima N, Fueyo J, et al. Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res. 2009; 69(23):8932-8940. doi: 10.1158/0008-5472.CAN-08-3873

[37] Garcia-Castro J, Alemany R, Cascallo M, et al. Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study. Cancer Gene Ther. 2010; 17(7):476-483. doi: 10.1038/cgt.2010.4

[38] Ahmed AU, Rolle CE, Tyler MA, et al. Bone marrow mesenchymal stem cells loaded with an oncolytic adenovirus suppress the anti-adenoviral immune response in the cotton rat model. Mol Ther. 2010; 18(10):1846-1856. doi: 10.1038/mt.2010.131

[39] Briolay T, Petithomme T, Fouet M, et al. Delivery of cancer therapies by synthetic and bio-inspired nanovectors. Mol Cancer. 2021; 20(1):55. doi: 10.1186/s12943-021-01346-2

[40] Shinojima N, Hossain A, Takezaki T, et al. TGF-beta mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells. Cancer Res. 2013; 73(7):2333-2344. doi: 10.1158/0008-5472.CAN-12-3086

[41] Ten Ham RMT, Hovels AM, Hoekman J, et al. What does cell therapy manufacturing cost? A framework and methodology to facilitate academic and other small-scale cell therapy manufacturing costings. Cytotherapy. 2020; 22(7):388-397. doi: 10.1016/j.jcyt.2020.03.432

[42] Strecanska M, Sekelova T, Smolinska V, Kuniakova M, Nicodemou A. Automated Manufacturing Processes and Platforms for Large-scale Production of Clinical-grade Mesenchymal Stem/Stromal Cells. Stem Cell Rev Rep. 2025; 21(2):372-389. doi: 10.1007/s12015-024-10817-8

[43] Ghasemi Darestani N, Gilmanova AI, Al-Gazally ME, et al. Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment. Cell Commun Signal. 2023; 21(1):43. doi: 10.1186/s12964-022-01017-1

[44] Wuchter P, Bieback K, Schrezenmeier H, et al. Standardization of Good Manufacturing Practice-compliant production of bone marrow-derived human mesenchymal stromal cells for immunotherapeutic applications. Cytotherapy. 2015; 17(2):128-139. doi: 10.1016/j.jcyt.2014.10.002

[45] Pittenger MF, Discher DE, Peault BM, et al. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019; 4:22. doi: 10.1038/s41536-019-0083-6

[46] Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009; 4(3):206-216. doi: 10.1016/j.stem.2009.02.001

[47] Cheng Z, Ou L, Zhou X, et al. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther. 2008; 16(3):571-579. doi: 10.1038/sj.mt.6300374

[48] Galipeau J, Sensebe L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell. 2018; 22(6):824-833. doi: 10.1016/j.stem.2018.05.004

[49] Hass R, Kasper C, Bohm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011; 9:12. doi: 10.1186/1478-811X-9-12

[50] Sukegawa M, Miyagawa Y, Kuroda S, et al. Mesenchymal stem cell origin contributes to the antitumor effect of oncolytic virus carriers. Mol Ther Oncol. 2024; 32(4):200896. doi: 10.1016/j.omton.2024.200896

[51] McKenna MK, Englisch A, Brenner B, et al. Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity. Mol Ther. 2021; 29(5):1808-1820. doi: 10.1016/j.ymthe.2021.02.004

[52] Zhang J, Chen H, Chen C, et al. Systemic administration of mesenchymal stem cells loaded with a novel oncolytic adenovirus carrying IL-24/endostatin enhances glioma therapy. Cancer Lett. 2021; 509:26-38. doi: 10.1016/j.canlet.2021.03.027

[53] Falagas ME, Pitsouni EI, Malietzis GA, Pappas G. Comparison of PubMed, Scopus, Web of Science, and Google Scholar: strengths and weaknesses. FASEB J. 2008; 22(2):338-342. doi: 10.1096/fj.07-9492LSF