{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:27:24Z","timestamp":1789464444367,"version":"build-2803163510"},"reference-count":280,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Med."],"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed and refractory haematological malignancies, producing durable clinical responses in patients with otherwise limited therapeutic options. Despite these advances, significant biological, clinical, and economic barriers continue to limit its broader application, particularly in solid tumours. This literature review critically evaluates recent developments in CAR-T cell therapy, with emphasis on areas that have received limited discussion in previous reviews. Multi-target CAR strategies, including bispecific, tandem, and pooled CAR-T cell approaches, are comparatively assessed with respect to antigen escape, manufacturing complexity, therapeutic efficacy, and safety. Current challenges in solid tumour treatment are examined through evidence from clinical trials, highlighting key obstacles such as antigen heterogeneity, the immunosuppressive tumour microenvironment, poor cellular trafficking, and treatment-related failures that have informed the development of next-generation CAR constructs. Emerging approaches to overcoming antigen loss, including \u03b3\u03b4 CAR-T cells, are reviewed alongside their current limitations, including restricted\n                    <jats:italic>ex vivo<\/jats:italic>\n                    expansion, donor variability, isolation challenges, and uncertain long-term persistence. The review also addresses the growing importance of improving affordability and accessibility through allogeneic \u201coff-the-shelf\u201d CAR-T products, genome editing technologies, automated manufacturing platforms, and rational combination therapies designed to enhance efficacy while reducing treatment costs. In addition, advances in toxicity prediction are evaluated, focusing on biomarkers beyond interleukin-6, including ferritin, C-reactive protein, soluble interleukin-2 receptor alpha, and multiparametric cytokine signatures for the early identification of severe cytokine release syndrome. Collectively, these developments demonstrate that future progress in CAR-T cell therapy will depend not only on enhancing antitumour efficacy but also on improving safety, accessibility, manufacturing efficiency, and equitable global implementation through evidence-based innovation.\n                  <\/jats:p>","DOI":"10.3389\/fmmed.2026.1931159","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:18:10Z","timestamp":1789460290000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The future directions of CAR-T Cell therapy: unlocking the potential of immunotherapy in cancer treatment"],"prefix":"10.3389","volume":"6","author":[{"given":"Angel Alberto","family":"Justiz-Vaillant","sequence":"first","affiliation":[{"name":"Department of Pathology\/Microbiology and Pharmacology, University of the West Indies","place":["St. Augustine, Trinidad and Tobago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Soodeen","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Microbiology and Pharmacology, University of the West Indies","place":["St. Augustine, Trinidad and Tobago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Arozarena-Fundora","sequence":"additional","affiliation":[{"name":"North Central Regional Health Authority (NCRHA)","place":["Trinidad and Tobago, Trinidad and Tobago"]},{"name":"Department of Clinical and Surgical Sciences, Faculty of Medical Sciences, The University of the West Indies","place":["St. Augustine, Trinidad and Tobago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick Eberechi","family":"Akpaka","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Microbiology and Pharmacology, University of the West Indies","place":["St. Augustine, Trinidad and Tobago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrashekhar","family":"Unakal","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Microbiology and Pharmacology, University of the West Indies","place":["St. Augustine, Trinidad and Tobago"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"200980","DOI":"10.1016\/j.omton.2025.200980","article-title":"Cost-effective strategies for CAR-T cell therapy manufacturing","volume":"33","author":"Abdo","year":"2025","journal-title":"Mol. 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