Allogeneic CAR-T cell therapies: Overcoming clinical challenges and therapeutic potential against tumors

Chimeric antigen receptor T-cell (CAR-T) therapy represents a major advance in cellular immunotherapy and has demonstrated substantial clinical benefit in relapsed or refractory B-cell malignancies. However, autologous CAR-T therapy remains constrained by manufacturing complexity, high cost, variability in product quality, and treatment delays that may compromise outcomes in rapidly progressing disease. Allogeneic “off-the-shelf” CAR-T cell approaches have emerged as a potential strategy to address these limitations by enabling standardized manufacturing, rapid availability, and scalable production. Nevertheless, these theoretical advantages must be carefully balanced against significant challenges, including alloreactivity, immune rejection, complex genome engineering requirements, and regulatory constraints. This review provides a critical and balanced overview of the advantages and limitations of allogeneic CAR-T cell therapy, with a particular focus on applications in solid tumors. We discuss key biological barriers, including tumor microenvironment-mediated immunosuppression, and evaluate current engineering strategies aimed at enhancing efficacy, along with emerging clinical data. Collectively, while allogeneic CAR-T therapies hold considerable promise, substantial scientific, technical, and regulatory challenges must be addressed before their widespread clinical implementation.