Next-generation CAR-T and CAR-NK cell therapies in hematologic malignancies: engineering for persistence, specificity, and safety

Chimeric antigen receptor (CAR) T-cell therapy has profoundly reshaped the therapeutic landscape for hematologic malignancies, achieving remarkable response rates in relapsed/refractory B-cell leukemias and lymphomas. Despite this success, significant challenges persist regarding long-term CAR-T cell persistence, precise tumor specificity, and the management of treatment-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Concurrently, CAR-Natural Killer (CAR-NK) cell therapy is emerging as a compelling alternative, offering inherent safety advantages, including a reduced risk of CRS and graft-versus-host disease (GvHD), alongside a promising “off-the-shelf” potential. This review examines the current state of CAR-T and CAR-NK cell therapies in hematologic malignancies, detailing advanced engineering strategies aimed at enhancing their persistence, improving tumor-specific targeting, and bolstering safety. It delves into innovations such as optimized CAR designs, cytokine and metabolic engineering, multi-antigen targeting, and the implementation of sophisticated safety switches. Future directions emphasize the integration of cutting-edge technologies, including advanced gene editing, non-viral delivery systems, and artificial intelligence (AI)-driven CAR design, alongside rational combination therapies, to achieve more durable, precise, and widely accessible treatments for hematologic cancers.