From T cells to NK cells and macrophages: progress and challenges in CAR-based therapies and the involved gene delivery systems

Chimeric antigen receptor (CAR)-based therapies have transformed the treatment of hematological malignancies, with CAR-T cell therapies establishing themselves as effective clinical options. Building on this success, recent research has expanded CAR engineering to natural killer (CAR-NK) cells and macrophages (CAR-M), aiming to address key limitations such as manufacturing complexity, safety concerns, and suboptimal efficacy against solid tumors. Advances in non-viral gene delivery systems have further progressed the field, providing alternatives to traditional viral vectors by enabling efficient, scalable, and less toxic CAR gene transfer. This review summarizes the evolution and latest developments in CAR-T, CAR-NK, and CAR-M therapies, with a focus on innovative non-viral delivery platforms. We highlight current clinical achievements, ongoing challenges, and the convergence of cell engineering and delivery approaches that are broadening the therapeutic potential of CAR technology. Continued progress in these areas can make personalized, targeted cancer immunotherapies more accessible, versatile, and beneficial for a wider patient population.