Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

Abstract Natural killer (NK) cells are an important contributor to cancer immunotherapy, but their antitumor efficacy remains suboptimal. While cytokine‐based priming shows promise in enhancing NK‐cell activity, its clinical translation faces many challenges, including coactivation of multiple cytokines, poor pharmacokinetics, and limited mechanistic understanding. Here, this work develops a polymeric micelle‐based IL‐15/IL‐2 codelivery system (IL‐15/2‐PEG‐PTMC) for NK‐cell activation. In vivo studies demonstrate that half‐life of IL‐15 and IL‐2 and the recruitment of NK cell within tumor tissue are significantly increased after PEG‐PTMC loading. Coupled with the coactivation effect of IL‐15 and IL‐2 conferred by this system, it noticeably delays the growth of tumors compared to conventional NK‐cell activation approach, that is free IL‐15 and IL‐2. It is also surprisingly found that cholesterol metabolism is highly involved in the NK cell activation by IL‐15/2‐PEG‐PTMC. Following stimulation with IL‐15/2‐PEG‐PTMC or IL‐15, NK cells undergo a series of cholesterol metabolism reprogramming, which elevates the cholesterol levels on NK cell membrane. This in turn promotes the formation of lipid rafts and activates immune synapses, effectively contributing to the enhancement of NK cell's antitumor activity. It is believed that it will open a new avenue for improving the efficacy of NK cell immunotherapy by regulating cholesterol metabolism.