Potential Application of CAR-NK Cells as an Ex Vivo Therapy for T-cell-related Diseases

Anticancer therapeutics have evolved from small-molecule drugs to monoclonal antibodies and, more recently, to cell and gene therapies (CGTs). This progress has been driven by the pursuit of greater drug specificity, potency, and safety. Recent breakthroughs in chimeric antigen receptor T-cell (CAR-T) therapy for B-cell hematologic malignancies have accelerated the development of CAR-X CGTs, including CAR-T, CAR-natural killer (CAR-NK), and CAR-macrophage approaches. In this article, we compare candidate CAR-X platforms for T-cell–related diseases, such as T-cell hematologic malignancies, and propose the most suitable modality. Therefore, we analyzed the advantages and limitations of CAR-T, CAR-NK, and CAR-macrophage therapies. In T-cell-related diseases, CAR-T therapy faces multiple challenges, including fratricide, T-cell aplasia, and substantial barriers to the generation of allogeneic CAR-T products. CAR-macrophage therapies, in contrast, are constrained by relatively limited efficacy. In contrast, CAR-NK cells do not cause fratricide or T-cell aplasia and can be manufactured efficiently as allogeneic, “off-the-shelf” products. Collectively, to sustain and extend the advances in CGT initiated by CAR-T cells in B-cell malignancies, prioritizing CAR-NK research infrastructure for T-cell–related diseases represents a rational and strategic approach.