Resveratrol Enhances CAR NK Cell Function in Cellular Immunotherapy of Non‐Hodgkin Lymphoma

ABSTRACT Resveratrol (RSV) is a dietary polyphenolic compound with anticancer property. However, its clinical translation as an anticancer chemotherapeutic agent is hindered by multiple challenges. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising immunotherapeutic strategy against refractory malignancies. The role of RSV in CAR NK cell therapy remains unexplored. This study pioneers the investigation of RSV's role in CAR NK immunotherapy. Specially, RSV preconditioning improved CAR NK cells’ resistance to oxidative stress, and augmented energetic metabolism in CAR NK cells. More importantly, the enhanced cytotoxicity against cancer cells of non‐Hodgkin lymphoma (NHL) and stronger cytokine secretions were observed in RSV‐treated anti‐CD19 CAR NK cells. In vivo tracking revealed RSV extended CAR NK tissue residency and enhanced therapeutic efficacy in NHL xenografts. RSV‐adjuvanted anti‐CD19 CAR NK therapy achieved an obvious reduction in intraperitoneal tumor burden and improvement in the mice survival. Our mechanistic investigation revealed that nuclear factor erythroid 2‐related factor 2 (NRF2) serves as a critical mediator in RSV‐induced functional augmentation of CAR NK cells. These findings established RSV as a potential polyphenol adjuvant capable of improving CAR NK therapy, providing a translatable strategy for polyphenols to overcome current limitations in cancer therapy.