Chimeric antigen receptor (CAR) natural killer (NK) cells represent a promising experimental cell therapy, but the molecular mechanism regulating their activity is not fully understood. In a new study, researchers led by Katy Rezvani, M.D., Ph.D., and Hind Rafei, M.D., identified a protein – cAMP response element modulator (CREM) – as a critical checkpoint regulator of CAR NK cells that, when upregulated, limits the effectiveness of CAR NK cells.
Researchers used CRISPR gene editing to target and knock out CREM, which significantly improved CAR NK cell function in multiple tumor models. The researchers clarified that this checkpoint is not exclusive to engineered CAR NK cells since it also impacted non-engineered NK cells, suggesting a broader regulatory mechanism limiting NK and T cell activation. This study suggests that inhibiting CREM is a promising strategy to enhance antitumor immune responses, highlighting the potential for genetic modifications to overcome immune suppression and improve NK cell therapies.