Facts and Hopes of Chimeric Antigen Receptor-Redirected Natural Killer T cells

Abstract Chimeric antigen receptor (CAR)-engineered invariant natural killer T cells (CAR-NKTs) are a novel cell platform for cancer immunotherapy. Unlike conventional T cells, NKTs are characterized by innate antitumor properties, minimal alloreactivity, and a unique ability to modulate the tumor microenvironment (TME). This article provides a comprehensive overview of preclinical and early clinical studies evaluating CAR-NKTs in both autologous and allogeneic clinical settings. We discuss the contributions of CAR signaling domains, cytokine co-expression, and other functional measures that correlate with CAR-NKT persistence, function, and metabolic fitness. We also discuss the critical role of immunocompetent animal models in elucidating the interactions of CAR-NKTs with the TME and other components of the immune system. Finally, we review strategies that combine CAR-NKTs with other therapeutic approaches to promote potential synergistic benefits in cancer patients.