Precision targeting and alternative effector cells: Revolutionizing CAR-based therapy for T-cell malignancies

T-cell malignancies are highly heterogeneous and associated with high relapse rate and poor prognosis. While chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable success in relapsed or refractory B-cell malignancies, its application in T-cell malignancies remains limited. Key challenges include shared surface antigen expression among CAR-T cells, normal T cells, and malignant T cells, leading to fratricide and T-cell aplasia, and the risk of tumor cell contamination during CAR-T manufacturing. This review summarizes recent advances in CAR-based therapies for T-cell malignancies, focusing on clinical translation barriers, emerging solutions, and future directions. We highlight promising target antigens under preclinical and clinical investigation, as well as alternative effector platforms, including natural killer (NK) cells, NKT cells, γδ T cells, and macrophages, that hold potential as next-generation CAR-expressing cellular therapeutics.