Focused Ultrasound-Responsive Artificial Killer Cells for Enhanced Closed-Loop Cancer Immunotherapy

Emerging immunotherapies have demonstrated remarkable potential in cancer treatment. However, persistent challenges including insufficient immune activation and limited tumor infiltration remain unresolved. Here, we introduce focused-ultrasound (FUS) responsive artificial killer cells (AKCs), a novel biomimetic system integrating functions of natural killer (NK) cells, dendritic cells (DCs) and macrophages for closed-loop tumor immunotherapy. AKCs consist of lanthanide nanoparticles integrated within a hybrid lipid membrane, which not only improves biocompatibility but also enables real-time monitoring through near-infrared (NIR) imaging. Compared to traditional liposomal formulations, AKCs demonstrate superior tumor targeting and retention properties, significantly improving the reliability of diagnostics and therapeutic efficacy. The innovative use of FUS allows for controlled release of copper cations, which, in conjunction with the recruitment of dendritic cells via RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted) cytokine release, transforms the immunosuppressive tumor microenvironment to immunologically active states. Cuproptosis induced by AKCs can significantly enhance tumor elimination efficacy. Tumor bearing mice exhibited prolonged survival and tumor regression with AKCs exhibiting superior tumor targeting and sustained antitumor effects. This research highlights a multifaceted approach to cancer immunotherapy, combining innate and adaptive immune activation mechanisms, thereby suggesting a promising direction for future advancements in targeted cancer therapies.