Smart control of CAR-T cells: emerging strategies for safer and more effective cancer immunotherapy

Chimeric Antigen Receptor (CAR)-T cell therapy has developed cancer immunotherapy but remains restricted by severe toxicities, antigen escape, and loss of efficacy in solid tumors. Recent advances in smart control systems aim to enhance the safety and precision of CAR-T therapies through tunable, reversible, and context-dependent mechanisms. These include the importance of inducible CAR expression, logic-gated receptors, and external control systems using drugs, light, or biomaterials. Synthetic biology approaches integrating sensor circuits and feedback loops are paving the way for programmable immunity, enabling dynamic adjustment of CAR-T activity in real time. The aim of this study is to review recent advances in strategies that enable smart controlled and designed activity of CAR-T cells for safer and more effective cancer immunotherapy. It seeks to summarize key molecular, genetic, and synthetic approaches designed to regulate CAR-T cell activation, persistence, and cytotoxicity with high precision.