{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:37:33Z","timestamp":1791805053170,"version":"4.3.4"},"reference-count":0,"publisher":"Association of Basic Medical Sciences of FBIH","issue":"10","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomol Biomed"],"abstract":"<jats:p>Cancer immunotherapy has transformed oncology by enabling targeted activation of antitumor immune responses in patients with relapsed or refractory malignancies. Among adoptive cell transfer (ACT) strategies, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a pivotal therapeutic advancement, genetically redirecting T lymphocytes to recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation. This review provides a comprehensive overview of the biological principles, design evolution, manufacturing platforms, clinical applications, resistance mechanisms, toxicities, and future directions of CAR-T cell therapy within cancer immunotherapy. Specifically, we examine the evolution of CAR architecture, spanning from first-generation constructs to advanced armored and fifth-generation platforms. Furthermore, we compare viral and non-viral gene delivery systems and discuss emerging approaches such as in vivo CAR engineering, allogeneic \"off-the-shelf\" products, logic-gated receptors, safety switches, and alternative immune-cell platforms, including natural killer (NK) cells and macrophages. CAR-T cell therapy has achieved its most profound clinical success in hematological malignancies, particularly in cluster of differentiation 19 (CD19)-positive B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma, reporting durable remission rates of approximately 60\u201390% in specific clinical contexts. However, broader clinical translation, particularly in solid tumors, remains constrained by challenges such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), antigen escape, tumor heterogeneity, poor trafficking, limited persistence, high manufacturing costs, and the immunosuppressive tumor microenvironment (TME). While next-generation strategies\u2014including clustered regularly interspaced short palindromic repeats\/CRISPR-associated protein 9 (CRISPR\/Cas9)-mediated editing, lipid nanoparticle (LNP)-based messenger ribonucleic acid (mRNA) delivery, bispecific CARs, and inducible suicide switches\u2014hold promise for improving safety, specificity, scalability, and accessibility, a significant number remain in preclinical or early-phase clinical development. Overall, CAR-T cell therapy represents a transformative \"living drug\" platform in oncology; however, its broader clinical utility is contingent upon improving durability, reducing toxicity, overcoming solid-tumor barriers, and validating next-generation technologies through robust, long-term clinical studies.<\/jats:p>","DOI":"10.17305\/bb.2026.14266","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T10:44:07Z","timestamp":1779792247000},"page":"1688-1705","source":"Crossref","is-referenced-by-count":3,"title":["CAR-T cell therapy in cancer immunotherapy \u2013 Biology, clinical successes, and emerging challenges: A review"],"prefix":"10.17305","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2196-6835","authenticated-orcid":false,"given":"Abdisa Tufa","family":"Bedada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2114-9325","authenticated-orcid":false,"given":"Mohammed","family":"Mehdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6855-2827","authenticated-orcid":false,"given":"Ousman","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6922","published-online":{"date-parts":[[2026,5,26]]},"container-title":["Biomolecules and Biomedicine"],"original-title":[],"link":[{"URL":"https:\/\/bjbms.org\/ojs\/index.php\/bjbms\/article\/download\/14266\/4205","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bjbms.org\/ojs\/index.php\/bjbms\/article\/download\/14266\/4205","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T22:01:43Z","timestamp":1782943303000},"score":1,"resource":{"primary":{"URL":"https:\/\/bjbms.org\/ojs\/index.php\/bjbms\/article\/view\/14266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":0,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.17305\/bb.2026.14266","relation":{},"ISSN":["2831-090X","2831-0896"],"issn-type":[{"value":"2831-090X","type":"electronic"},{"value":"2831-0896","type":"print"}],"subject":[],"published":{"date-parts":[[2026,5,26]]}}}