Buddy-CAR NK cells: IL-7/IL-7Rα cytokine circuit drives self-activation and boosts T cell immunity

Adoptive cell therapy has revolutionized the treatment of hematologic malignancies, yet efficacy in solid tumors remains limited by poor persistence, immunosuppressive tumor microenvironment (TME), and toxicity concerns. Natural killer (NK) cells provide an attractive alternative to T cells, offering potent cytotoxicity with reduced risk of cytokine release syndrome, neurotoxicity, and graft versus host disease. However, NK cell therapies are hindered by a short lifespan with limited in vivo persistence. Here, we establish Buddy-CAR, a first-in-class NK cell platform that integrates the IL-7/IL-7Rα cytokine circuit to create self-sustaining NK cells that also amplify T-cell immunity. This novel dual-function design reprograms NK cells into living immune hubs that maintain metabolic fitness and persistence while enhancing CAR-T expansion, effector function, and resistance to exhaustion. Mechanistically, Buddy-CAR engaged STAT1/STAT5 signaling axis and synergized with STING activation, driving heightened interferon responses. This self-sustaining and immunomodulatory design improved tumor control across models of pancreatic cancer, acute myeloid leukemia, and mixed xenografts. These findings establish Buddy-CAR NK cells as a versatile platform that integrates NK cell intrinsic fitness with extrinsic T cell support, offering a promising strategy for overcoming immune suppression in solid and hematologic malignancies.