Chimeric antigen receptor T cell therapy: Revolutionizing cancer treatment

Chimeric antigen receptor T (CAR-T) cell therapy represents a major advance in cancer immunotherapy, offering targeted treatment options, particularly for hematologic malignancies. This review comprehensively explores the structural evolution, production processes, and cytotoxic mechanisms underlying CAR-T function. Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens. Key structural components such as antigen recognition domains, spacers, transmembrane, and intracellular domains are optimized to enhance specificity, persistence, and cytotoxicity. CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation, Fas/Fas ligand signaling, and cytokine secretion. Over time, the development of second- to fifth-generation CARs has incorporated costimulatory molecules, transcriptional regulation, and logic-gated control to improve efficacy and safety. Additionally, novel engineering strategies such as dual CARs, tandem CARs, SynNotch systems, and universal or inhibitory CARs have expanded antigen targeting and reduced off-tumor toxicity. Emerging gene delivery technologies, including viral vectors, transposons, CRISPR/Cas9, and RNA-based electroporation, are improving CAR-T production. Despite notable clinical success, particularly in CD19- and B-cell maturation antigen-targeted therapies, CAR-T applications face challenges, including cell exhaustion, antigen escape, and therapy-induced toxicities, such as cytokine release syndrome and neurotoxicity. Ongoing efforts in engineering innovation, clinical trials, and regulatory support continue to shape CAR-T therapy into a safer, more precise tool for cancer treatment. This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.