In the fight against cancer, CAR-T cells have achieved remarkable results in treating blood cancers. However, they have proven largely ineffective against solid tumors. CAR-NKT cells, on the other hand, possess innate properties that make them particularly well-equipped to combat solid tumors. Specifically, they express a T cell receptor that recognizes glycolipid antigens presented by CD1d molecules. CAR-NKT cells effectively eliminate CD1d-expressing M2 macrophages in the tumor microenvironment. These macrophages promote tumor growth and suppress immune responses, making their elimination essential for strengthening antitumor immunity. By targeting these cells, CAR-NKT therapy effectively reprograms the tumor microenvironment from a pro-tumor to an anti-tumor state. CAR-NKT cells promote epitope spreading, a process by which the immune system recognizes and attacks new targets, activating T-cell responses. Researchers further demonstrated that combining CAR-NKT cells with PD1 blockade significantly enhances their antitumor activity, and that this activity can be further strengthened by vaccination approaches, such as those using dendritic cells loaded with alpha-galactosylceramide.
