Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses

T cell engagers (TCEs) are transformational oncology therapies but are limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce fewer cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs). However, why NK cells secrete fewer cytokines, such as tumor necrosis factor (TNF), and how NKCEs perform directly against TCEs remains unclear. Here, we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate interleukin (IL)-2, thereby increasing their potency and durability. Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and distinct therapeutic benefits. Our results provide a blueprint for the development of multifunctional NKCEs, which may serve as an alternative to current TCE therapies.