Revolutionizing immunotherapy: The next frontier in CAR T-cell engineering.

Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a groundbreaking immunotherapy, offering new hope for cancer treatment, particularly in hematologic malignancies. This review explores the development of CAR T-cell therapy from its first-generation design, which laid the foundational structure, to advanced fifth-generation CARs that integrate sophisticated synthetic biology. Each generation of CARs has introduced critical improvements, such as the incorporation of costimulatory domains, dual signaling pathways, and cytokine release mechanisms to enhance T-cell activation, persistence, and efficacy. Current applications of CAR T-cell therapy have seen significant success in treating cancers like acute lymphoblastic leukemia and diffuse large B-cell lymphoma, with several therapies gaining regulatory approval. However, challenges persist in targeting solid tumors due to the immunosuppressive tumor microenvironment and antigen heterogeneity. Ongoing clinical trials and research are focused on overcoming these barriers through next-generation CAR designs, novel antigen targets, and combination therapies. The review highlights recent advancements, emerging targets, and the potential of CAR T-cell therapy to revolutionize cancer treatment, paving the way for more effective and personalized approaches.