{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T20:09:15Z","timestamp":1794254955675,"version":"4.9.0"},"reference-count":45,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Serbian Ministry of Science","award":["451-03-47\/2023-01\/200111"],"award-info":[{"award-number":["451-03-47\/2023-01\/200111"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chimeric antigen receptor (CAR)-engineered immune cells, particularly CAR T lymphocytes and CAR natural killer (NK) cells, have revolutionized cancer immunotherapy. However, their therapeutic efficacy and safety can be influenced by the tumor microenvironment, particularly the presence of mesenchymal stem cells (MSCs). MSCs are immunomodulatory cells which can alter the function of tumor-infiltrated immune cells in both supportive and suppressive ways. Results obtained in recently conducted experimental studies demonstrate that MSCs modulate proliferation, cytotoxicity, cytokine production and anti-tumor activity in CAR-expressing immune cells in both a juxtacrine and a paracrine manner. While MSCs can enhance CAR cell viability and persistence through trophic support, they may also impair cytotoxic function and promote an immunosuppressive phenotype under certain conditions. Understanding the dualistic nature of MSCs in CAR-based immunotherapy for malignant diseases is critical for optimizing clinical outcomes. Additionally, MSCs may serve as vehicles for targeted delivery of immunomodulatory agents, and should be considered as active components in the design of next-generation CAR-based immunotherapies. Accordingly, in this review article we emphasize molecular and cellular mechanisms involved in MSC-dependent modulation of CAR-expressing immune cells, paving the way for more efficient CAR-based immunotherapy for malignant diseases.<\/jats:p>","DOI":"10.3390\/cells14130978","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effects of Mesenchymal Stem Cells on Functions of Chimeric Antigen Receptor-Expressing T Lymphocytes and Natural Killer Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Vladislav","family":"Volarevic","sequence":"first","affiliation":[{"name":"Departments of Genetics, Microbiology and Immunology, Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl Randall","family":"Harrell","sequence":"additional","affiliation":[{"name":"Regenerative Processing Plant, LLC, 34176 US Highway 19 N, Palm Harbor, FL 34684, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2742-8165","authenticated-orcid":false,"given":"Aleksandar","family":"Arsenijevic","sequence":"additional","affiliation":[{"name":"Departments of Genetics, Microbiology and Immunology, Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin","family":"Djonov","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Volarevic","sequence":"additional","affiliation":[{"name":"Departments of Psychology, Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/0006-291X(87)90502-X","article-title":"Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions","volume":"149","author":"Kuwana","year":"1987","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Shin, M.H., Oh, E., Kim, Y., Nam, D.H., Jeon, S.Y., Yu, J.H., and Minn, D. (2023). Recent Advances in CAR-Based Solid Tumor Immunotherapy. Cells, 12.","DOI":"10.3390\/cells12121606"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.7150\/ijbs.34213","article-title":"Current Progress in CAR-T Cell Therapy for Solid Tumors","volume":"15","author":"Ma","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Rotolo, R., Leuci, V., Donini, C., Cykowska, A., Gammaitoni, L., Medico, G., Valabrega, G., Aglietta, M., and Sangiolo, D. (2019). CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112839"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4017","DOI":"10.1182\/blood-2014-12-580068","article-title":"CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia","volume":"125","author":"Maude","year":"2015","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1053\/j.seminhematol.2023.11.007","article-title":"CD19 CAR-T cell therapy for relapsed or refractory diffuse large B cell lymphoma: Why does it fail?","volume":"60","author":"Kinoshita","year":"2023","journal-title":"Semin Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mishra, A.K., Gupta, A., Dagar, G., Das, D., Chakraborty, A., Haque, S., Prasad, C.P., Singh, A., Bhat, A.A., and Macha, M.A. (2023). CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond. Vaccines, 11.","DOI":"10.3390\/vaccines11111721"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chen, X., Li, P., Tian, B., and Kang, X. (2022). Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1079181"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yan, Z., Zhang, H., Cao, J., Zhang, C., Liu, H., Huang, H., Cheng, H., Qiao, J., Wang, Y., and Wang, Y. (2021). Characteristics and Risk Factors of Cytokine Release Syndrome in Chimeric Antigen Receptor T Cell Treatment. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.611366"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Buciuc, A.G., Tran, S., Weber, M., Padilla, V., Rueda-Lara, M., and Espinel, Z. (2025). Immune Effector Cell-Associated Neurotoxicity Syndrome After CAR T-Cell Therapy and Other Psychiatric Manifestations: A Review and Case Series. J. Clin. Med., 14.","DOI":"10.3390\/jcm14051451"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e17616","DOI":"10.7717\/peerj.17616","article-title":"Functional variation among mesenchymal stem cells derived from different tissue sources","volume":"12","author":"Yi","year":"2024","journal-title":"PeerJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.tips.2020.06.009","article-title":"Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential","volume":"41","author":"Song","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s13045-021-01208-w","article-title":"Mesenchymal stem\/stromal cells in cancer therapy","volume":"14","author":"Lan","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/s41419-022-05034-x","article-title":"Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: A next generation therapeutic tool?","volume":"13","author":"Kou","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mishra, H.K., and Kalyuzhny, A. (2024). Revolutionizing Cancer Treatments through Stem Cell-Derived CAR T Cells for Immunotherapy: Opening New Horizons for the Future of Oncology. Cells, 13.","DOI":"10.3390\/cells13181516"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s12964-023-01191-4","article-title":"The role of MSCs and CAR-MSCs in cellular immunotherapy","volume":"21","author":"Yan","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.stem.2023.02.009","article-title":"Advancing cell-based cancer immunotherapy through stem cell engineering","volume":"30","author":"Li","year":"2023","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"60752","DOI":"10.18632\/oncotarget.11354","article-title":"Mesenchymal stromal cells (MSCs) and colorectal cancer: A troublesome twosome for the anti-tumour immune response?","volume":"7","author":"Heijltjes","year":"2016","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Poggi, A., Varesano, S., and Zocchi, M.R. (2018). How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00262"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41408-021-00459-7","article-title":"CAR-T cell therapy: Current limitations and potential strategies","volume":"11","author":"Sterner","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_21","first-page":"2313","article-title":"Effects of CAR structure and culture conditions on memory CAR-T cells","volume":"25","author":"Pei","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41392-021-00823-w","article-title":"T cell receptor (TCR) signaling in health and disease","volume":"6","author":"Shah","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Harrell, C.R., Volarevic, A., Djonov, V.G., Jovicic, N., and Volarevic, V. (2021). Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212429"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41419-025-07443-0","article-title":"Engineered mesenchymal stem\/stromal cells against cancer","volume":"16","author":"Shi","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/sctm.18-0117","article-title":"Mesenchymal Stem Cell Administration Attenuates Colon Cancer Progression by Modulating the Immune Component within the Colorectal Tumor Microenvironment","volume":"8","author":"Usunier","year":"2019","journal-title":"Stem Cells Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1158\/1078-0432.CCR-20-2188","article-title":"Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis","volume":"27","author":"Holthof","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114857","DOI":"10.1016\/j.taap.2019.114857","article-title":"Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells","volume":"387","author":"Chiou","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Holthof, L.C., and Mutis, T. (2020). Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance. Cancers, 12.","DOI":"10.3390\/cancers12040988"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hombach, A.A., Geumann, U., G\u00fcnther, C., Hermann, F.G., and Abken, H. (2020). IL7-IL12 Engineered Mesenchymal Stem Cells (MSCs) Improve A CAR T Cell Attack Against Colorectal Cancer Cells. Cells, 9.","DOI":"10.3390\/cells9040873"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101747","DOI":"10.1016\/j.xcrm.2024.101747","article-title":"A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2R\u03b1 strengthens T cell-mediated anti-tumor therapies","volume":"5","author":"Wu","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e001419","DOI":"10.1136\/jitc-2020-001419","article-title":"Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity","volume":"8","author":"Zanetti","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1016\/j.ymthe.2021.02.004","article-title":"Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity","volume":"29","author":"McKenna","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Chen, F., Wu, K., Lin, S., Cui, J., Chen, X., Zeng, Z., Yuan, N., Fang, M., Liu, X., and Chen, Y. (2024). Enhancing Tumor Immunity with IL-12 and PD-1 Blockade: A Strategy for Inducing Robust Central Memory T Cell Responses in Resistant Cancer Model. Antibodies, 13.","DOI":"10.3390\/antib13040094"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1507","DOI":"10.1002\/cti2.1507","article-title":"Optimisation of a primary human CAR-NK cell manufacturing pipeline","volume":"13","author":"Pfefferle","year":"2024","journal-title":"Clin. Transl. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e27196","DOI":"10.1016\/j.heliyon.2024.e27196","article-title":"CAR-NK cells in combination therapy against cancer: A potential paradigm","volume":"10","author":"Li","year":"2024","journal-title":"Heliyon"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e561","DOI":"10.1097\/HS9.0000000000000561","article-title":"Bone Marrow Mesenchymal Stromal Cell-mediated Resistance in Multiple Myeloma Against NK Cells can be Overcome by Introduction of CD38-CAR or TRAIL-variant","volume":"5","author":"Holthof","year":"2021","journal-title":"Hemasphere"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12935-021-01836-9","article-title":"Mesenchymal stem cells and cancer therapy: Insights into targeting the tumour vasculature","volume":"21","author":"Aravindhan","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"351","DOI":"10.15283\/ijsc20146","article-title":"Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight","volume":"14","author":"Ghollasi","year":"2021","journal-title":"Int. J. Stem Cells."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e348","DOI":"10.1038\/bcj.2015.73","article-title":"Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts","volume":"5","author":"Aliperta","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41417-018-0062-x","article-title":"Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors","volume":"27","author":"Golinelli","year":"2020","journal-title":"Cancer Gene Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101240","DOI":"10.1016\/j.tranon.2021.101240","article-title":"Anti-GD2 CAR MSCs against metastatic Ewing\u2019s sarcoma","volume":"15","author":"Golinelli","year":"2022","journal-title":"Transl. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1111\/cas.13334","article-title":"Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential","volume":"108","author":"Lee","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yamaguchi, N., Horio, E., Sonoda, J., Yamagishi, M., Miyakawa, S., Murakami, F., Hasegawa, H., Katahira, Y., Mizoguchi, I., and Fujii, Y. (2024). Immortalization of Mesenchymal Stem Cells for Application in Regenerative Medicine and Their Potential Risks of Tumorigenesis. IJMS, 25.","DOI":"10.3390\/ijms252413562"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1111\/jcmm.12264","article-title":"Gamma irradiation preserves immunosuppressive potential and inhibits clonogenic capacity of human bone marrow-derived mesenchymal stromal cells","volume":"18","author":"Riewaldt","year":"2014","journal-title":"J. Cell Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s12015-021-10163-5","article-title":"Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Preclinical Animal Models of Tumor Growth: Systematic Review and Meta-Analysis","volume":"18","author":"Bailey","year":"2022","journal-title":"Stem Cell Rev. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:58:35Z","timestamp":1760032715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":45,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["cells14130978"],"URL":"https:\/\/doi.org\/10.3390\/cells14130978","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,25]]}}}