Engineering CAR T NK and NKT cell therapies to target cancer stem cells and overcome stem like resistance

Cancer stem cells (CSCs) represent a critical subpopulation within tumors, driving progression, metastasis, and, notably, resistance to conventional therapies. This inherent recalcitrance underscores an urgent need for targeted eradication strategies. Chimeric Antigen Receptor (CAR)-based cellular immunotherapies, including CAR-T, CAR-NK, and CAR-NKT cells, have revolutionized the treatment of hematological malignancies and are now emerging as potent tools against CSCs in solid tumors. This review provides a comprehensive overview of CSC biology, the foundational principles of CAR engineering, and the current clinical landscape of these cellular immunotherapies. It delves into the specific challenges encountered when targeting CSCs, such as tumor heterogeneity, the pervasive immunosuppressive tumor microenvironment, and the risk of on-target/off-tumor toxicities. Furthermore, the report explores advanced engineering strategies, including dual-targeting and logic-gated CARs, the strategic modulation of CSC metabolism, and the transformative potential of multi-omics integration and artificial intelligence. By synthesizing current knowledge and highlighting innovative approaches, this review aims to illuminate the path toward overcoming stem-like resistance and achieving durable cancer remission through engineered cellular immunotherapies.