“Activation‐Resistance Elimination” Regulation by Lanthanide/Transition Metal Ion‐Coordinated Nanostructures Intensifies Cuproptosis and Tumor Immunotherapy

ABSTRACT The therapeutic efficacy of cuproptosis is constrained by its insufficient activation and resistance mechanisms. Here, a lanthanide/transition metal ion‐coordinated nanoparticle, La‐Cu@Lap/IWR‐1, with optimized coordination, has been proven to achieve remarkable results in realizing comprehensive resistance‐eliminating cuproptosis activation. La 3+ not only enhances Cu 2+ ‐mediated multiple enzyme‐mimetic activities via coordination to amplify oxidative stress but also disrupts lysosomal acidification to improve copper ion availability. Moreover, combined with lapatinib (Lap), it alleviates the shielding effect of mediator of cell motility 1 (MEMO1) on Cu 2+ , significantly strengthening the cuproptosis activation efficacy. Meanwhile, the released Wnt inhibitor IWR‐1 can not only inhibit the Wnt/β‐catenin signaling pathway that is concomitantly activated during cuproptosis induction to weaken the oxidative stress tolerance of tumor cells but also synergize with Lap to downregulate hypoxia‐inducible factor 1α (HIF‐1α) expression, thereby effectively eliminating cuproptosis resistance. This comprehensive cuproptosis not only triggers significant immunogenic cell death but also synchronously inhibits key steps of tumor metastasis, such as epithelial‐mesenchymal transition and extracellular matrix remodeling. This work proposes a therapeutic strategy for achieving comprehensive resistance‐eliminating cuproptosis activation using lanthanide/transition metal ion coordination nanomaterials, providing a new entry point for tumor therapy.