Beyond CAR-T: Advancements in CAR-NK and CAR-NKT Therapies for Cancer Treatment

Abstract

Chimeric Antigen Receptor (CAR) technologies have transformed cancer immunotherapy, with CAR-T cell therapies demonstrating remarkable success in hematological malignancies. However, their clinical application is hindered by severe toxicities, high manufacturing costs, antigen heterogeneity, and limited efficacy in solid tumors due to poor infiltration and the immunosuppressive tumor microenvironment (TME). CAR-NK therapies have emerged as a promising alternative, offering an innate immune-based approach with lower toxicity, broader tumor recognition, and the potential for scalable "off-the-shelf" products. Despite these advantages, CAR-NK cells face challenges such as limited persistence, susceptibility to TME suppression, and lower expansion capabilities. Engineering strategies, including IL-15 expression, chemokine receptor upregulation, and CAR-independent mechanisms, are being explored to enhance their therapeutic potential in solid tumors. Additionally, CAR-NKT cells provide a hybrid approach, combining T and NK cell features to target both protein and glycolipid antigens while exhibiting improved infiltration and TME modulation. Early clinical trials suggest that CAR-NK and CAR-NKT therapies may address key limitations of CAR-T therapies, particularly in solid tumors, but further research is required to optimize their persistence, tumor specificity, and clinical scalability. This review explores the mechanistic differences between CAR-T and CAR-NK therapies, their respective strengths and limitations, and the potential of CAR-NKT cells as an emerging strategy to expand the reach of immunotherapy.