Toward the next generation of CAR T cell therapies for cancer.

With seven products approved by the US Food and Drug Administration (FDA) for 15 indications and more than 2,600 active clinical trials, chimeric antigen receptor (CAR) T cell therapy is firmly established as an effective therapeutic modality for cancer treatment, and promising early data demonstrate its potential in autoimmune diseases. Key challenges facing the field include extending efficacy to solid tumors and reducing the cost and complexity of manufacturing to improve patient access. In this review, we summarize the clinical lessons learned from the now substantial experience with commercial CAR T cells and clinical trials and discuss three waves shaping next-generation development: multi-engineered and logic-gated CAR T cells, rational combination strategies, and in vivo CAR T cell generation. By integrating clinical experience with emerging strategies, we highlight where CAR T cell therapy has succeeded, where current approaches remain insufficient, and how next-generation cell therapies may be designed to overcome these barriers.