Cytokine-based NK cell engineering for cancer immunotherapy

Natural killer (NK) cells are critical effector cells of the innate immune system and play essential roles in antiviral defense and antitumor immunity. In recent years, they have emerged as a major focus in the field of cancer immunotherapy. Cytokines constitute the fundamental molecular basis for regulating NK cell development, survival, proliferation, and effector functions, and also serve as key modulatory tools in NK cell engineering. This review summarizes recent progress in cytokine-driven NK cell engineering strategies and their applications in immunotherapy. It outlines the key cytokines associated with NK cell biology and the signaling pathways through which they regulate NK cell proliferation, activation, cytotoxicity, cytokine secretion, and the induction of cytokine-induced memory-like (CIML) NK cells. It further examines cytokine-based engineering strategies, with particular emphasis on IL-15-mediated support of NK cell expansion, functional maintenance, and persistence, including cytokine-supported culture systems, secreted IL-15, membrane-bound IL-15 (mbIL-15), and IL-15/IL-15Rα fusion formats. Future advances in precise signal modulation, controllable expression systems, and multi-cytokine synergistic strategies may help optimize therapeutic efficacy and facilitate the transition of NK cell therapy from empirical expansion approaches toward programmable signaling design.