From molecular design to clinical translation: dual-targeted CAR-T strategies in cancer immunotherapy

The pathogenesis of tumors involves various abnormalities at both the cellular and genetic levels. Chimeric antigen receptor (CAR)-T cell immunotherapy has emerged as a transformative treatment strategy that effectively addresses these challenges. While CAR-T therapy has shown remarkable success in treating hematological malignancies, limitations have been identified, particularly in single antigen-targeting CAR-T therapies. These limitations include antigenic mutation or loss, reduced efficacy against leukemia, and poor results in solid tumors due to factors like low CAR-T cell persistence, limited tumor infiltration, rapid cell exhaustion, the suppressive tumor microenvironment, and heterogeneous tumor antigen expression. In recent years, multi-antigen targeted CAR-T therapies have garnered significant attention for their potential to prevent tumor relapse and progression. This review outlines the fundamental design of dual CAR structures and summarizes the major advancements in both preclinical studies and clinical trials of dual-targeted CAR-T cell therapy, categorized by cancer type. Additionally, it discusses the challenges associated with dual-targeted CAR-T therapy and the strategies to enhance its efficacy and applicability in treating both hematologic and solid tumors. In conclusion, the progress in dual-targeted CAR-T cell therapy presents a promising therapeutic avenue for multiple malignancies, offering insights into future modifications of immunotherapy to advance the field.