{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:06Z","timestamp":1792789086617,"version":"4.5.0"},"reference-count":197,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Burjeel Cancer Institute, Abu Dhabi, United Arab Emirates"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of hematological malignancies, yet its application in solid tumors remains constrained by unique biological and logistical barriers. Objective: This review critically examines the evolving landscape of CAR T-cell therapy in solid malignancies, with a focus on antigen heterogeneity, the immunosuppressive tumor microenvironment, and risks of on-target, off-tumor toxicity. Methods: We outline recent advances in CAR engineering, including co-stimulatory optimization, dual- and multi-antigen targeting, armored CARs, and gene-edited constructs designed to enhance persistence and anti-tumor activity. Clinical progress is highlighted by recent FDA approvals of genetically modified T-cell therapies in synovial sarcoma and melanoma, underscoring the potential for broader solid tumor application. Additionally, we synthesize early-phase clinical trial findings across multiple solid tumor types (e.g., lung, colorectal, ovarian, glioblastoma), and discuss innovative approaches such as regional delivery, checkpoint blockade combinations, and incorporation of chemokine receptors for improved tumor infiltration. The review also considers future strategies, including artificial intelligence-guided target discovery and rational trial design to overcome translational bottlenecks. Conclusions: With expanding clinical experience and continued technological innovation, CAR T-cell therapy is steadily transitioning from an experimental strategy to a therapeutic reality in solid tumors, poised to reshape the future of cancer immunotherapy.<\/jats:p>","DOI":"10.3390\/cancers17172898","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T15:15:57Z","timestamp":1756912557000},"page":"2898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0974-1852","authenticated-orcid":false,"given":"Saeed","family":"Rafii","sequence":"first","affiliation":[{"name":"Department of Oncology, Mediclinic City Hospital, Dubai P.O. Box 505004, United Arab Emirates"},{"name":"Emirates Oncology Society, Dubai P.O. Box 6600, United Arab Emirates"},{"name":"Gulf Cancer Society, P.O. Box 26733, Alsafa 13128, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Mukherji","sequence":"additional","affiliation":[{"name":"Department of Oncology, Clemenceau Medical Center, Dubai 112963, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9671-685X","authenticated-orcid":false,"given":"Ashok Sebastian","family":"Komaranchath","sequence":"additional","affiliation":[{"name":"Department of Oncology, Burjeel Hospital Oman, 3521 Way, Muscat 112-1465, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7740-6963","authenticated-orcid":false,"given":"Charbel","family":"Khalil","sequence":"additional","affiliation":[{"name":"Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faryal","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6145-4466","authenticated-orcid":false,"given":"Siddig Ibrahim","family":"Abdelwahab","sequence":"additional","affiliation":[{"name":"Health Research Centre, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Abyad","sequence":"additional","affiliation":[{"name":"Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4182-065X","authenticated-orcid":false,"given":"Ahmad Y.","family":"Abuhelwa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice and Pharmacotherapeutics, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakshmikanth","family":"Gandikota","sequence":"additional","affiliation":[{"name":"Immuneel Therapeutics Pvt. Ltd., 8th Floor, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Health City, Hosur Rd, Bommasandra Industrial Area, Bommasandra, Bengaluru 560099, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3819-0500","authenticated-orcid":false,"given":"Humaid O.","family":"Al-Shamsi","sequence":"additional","affiliation":[{"name":"Emirates Oncology Society, Dubai P.O. Box 6600, United Arab Emirates"},{"name":"Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Harvard Medical School, Harvard University, Boston, MA 20138, USA"},{"name":"College of Medicine, Ras Al Khaimah Medical and Health Sciences University, Al Juwais, Al Qusaidat, Ras Al Khaimah 11172, United Arab Emirates"},{"name":"College of Medicine, Gulf Medical University, Ajman P.O. Box 4184, United Arab Emirates"},{"name":"College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"N. Engl. J. 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