Universal CAR-T cell therapy: overcoming key hurdles on the path to off-the-shelf adoption

Chimeric antigen receptor (CAR) T cells have revolutionized oncology, delivering unprecedented clinical responses in patients with refractory B-cell malignancies. However, the traditional autologous paradigm – encompassing patient-specific leukapheresis, genetic modification, and extensive ex vivo expansion – imposes severe constraints on manufacturing timelines, costs, and global scalability. Allogeneic universal CAR-T (uCAR-T) reimagines this therapeutic unit as an “off-the-shelf” cellular medicine, utilizing healthy donor-derived cells produced in standardized batches to overcome the bottlenecks of individualized therapy. Over the past decade, the field has transitioned from foundational proof-of-concept studies in murine models to sophisticated early-phase human clinical trials. This review delineates the core biological and engineering principles of uCAR-T, specifically focusing on the genomic strategies employed to mitigate graft-versus-host disease (GvHD) and host-versus-graft disease (HvGD). We synthesize pivotal preclinical and clinical data alongside a comprehensive overview of the current clinical landscape. Furthermore, we highlight the primary translational hurdles remaining: ensuring durable CAR-T persistence and navigating the complexities of innate and adaptive immune rejection. We explore the potential for combination immunotherapies and specialized CAR architectures designed to penetrate solid tumors. Ultimately, uCAR-T is poised to democratize cellular immunotherapy, offering a scalable and transformative therapeutic perspective across diverse disease indications.