Resistance to CAR-based cell therapy: Mechanisms and overcoming strategies

Chimeric antigen receptor (CAR)-based cell therapy holds great promise for the treatment of both hematological malignancies and solid tumors. However, primary and acquired resistance to CAR-based cell therapy remains a key obstacle to achieving effective and durable immunotherapy responses. Unlike small molecules or antibodies, CAR-engineered immune cells offer unique opportunities to design therapeutic agents, thereby enabling the improved products with potential to overcome multiple therapy resistance mechanisms. Therefore, elucidating the mechanisms of resistance to CAR-based cell therapy is crucial for the development of the next-generation CAR-based cell therapy. In this review, we outline the biological rationale of CAR-T, CAR-natural killer (NK), and CAR-macrophages, as well as other emerging CAR-based cell therapies. We focus on the mechanisms of resistance to CAR-based cell therapy, involving structural and functional defects of CAR products, tumor-intrinsic factors, and susceptibility of CAR-engineered cells to the hostile tumor microenvironment. We discuss key strategies to overcome multiple resistance mechanisms, such as targeting multiple antigens, optimizing CAR design and function, modifying the immunosuppressive tumor microenvironment, and developing combination treatment strategies. By systematically dissecting these multifaceted challenges, this review will provide insights for optimizing CAR-based cell therapy to overcome resistance and improve treatment efficacy.