{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:36:59Z","timestamp":1792442219679,"version":"4.5.0"},"reference-count":142,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Adoptive cell therapies (ACTs) have revolutionized cancer treatment by harnessing the specificity and potency of T lymphocytes. Chimeric antigen receptor (CAR)-T cells have achieved landmark successes in B-cell malignancies and multiple myeloma. Tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells offer complementary strategies to target solid tumors and intracellular antigens. Despite these advances, ACTs face challenges including cytokine release syndrome, neurotoxicity, on-target\/off-tumor effects, manufacturing scalability, and immunosuppressive tumor microenvironments. Innovative strategies, such as dual-antigen targeting, localized delivery, checkpoint blockade combinations, gene-editing, and machine-learning-guided antigen discovery, are being used to mitigate toxicity, enhance efficacy, and streamline production. As CAR-T, TIL, and TCR modalities converge with advances in manufacturing and computational biology, the next generation of \u201cliving drugs\u201d promises broader applicability across hematologic and solid tumors, improved safety profiles, and better treatment outcomes for patients. This review details the evolution of ACTs from first-generation CAR constructs to next-generation \u201carmored\u201d designs. It also focuses on the development and clinical deployment of TIL and TCR therapies. Furthermore, it synthesizes mechanisms, pivotal clinical trial outcomes, and ongoing challenges of ACTs. It also highlights strategies that will drive broader, safer, and more durable applications of these therapies across hematologic and solid tumors.<\/jats:p>","DOI":"10.3390\/medsci13030190","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T16:27:33Z","timestamp":1757953653000},"page":"190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Advances in Adoptive Cell Therapies in Cancer: From Mechanistic Breakthroughs to Clinical Frontiers and Overcoming Barriers"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-8158","authenticated-orcid":false,"given":"Syed Arman","family":"Rabbani","sequence":"first","affiliation":[{"name":"RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"El-Tanani","sequence":"additional","affiliation":[{"name":"RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahia","family":"El-Tanani","sequence":"additional","affiliation":[{"name":"Royal Cornwall Hospital, NHS Trust, Truro TR1 3LJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Amity Institute of Pharmacy, Amity University, Haryana 122412, India"},{"name":"Department of Pharmacy, Jagannath University, Haryana 124507, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrestha","family":"Sharma","sequence":"additional","affiliation":[{"name":"Amity Institute of Pharmacy, Amity University, Haryana 122412, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Ahmed","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6318-6506","authenticated-orcid":false,"given":"Suhel","family":"Parvez","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9519-6338","authenticated-orcid":false,"given":"Alaa A. A.","family":"Aljabali","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1209-0643","authenticated-orcid":false,"given":"Mohammad I.","family":"Matalka","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 21163, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9549-8504","authenticated-orcid":false,"given":"Manfredi","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"ref_1","unstructured":"Amjad, M.T., Chidharla, A., and Kasi, A. 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