Programmed Lung Metastasis Immunotherapy via Cascade‐Responsive Cell Membrane‐Mimetic Copolymer‐Wrapped Nanoraspberry‐Mediated Elesclomol‐Copper Delivery

Abstract T lymphocytes play a central role in immunotherapy, utilizing physical interactions to actively inhibit the development of metastases. However, tumor immune privilege and heterogeneity pose challenges by protecting against immune attacks and limiting immune cell infiltration into tumors, particularly in invasive metastatic clusters. Here, a tumor penetrating magnetic particles (TUP) containing the cascade‐responsive cell membrane‐mimetic copolymer (zwitterionic 2‐methacryloyloxyethyl phosphorylcholine‐co‐3‐hydroxypyridin‐4‐one, PH) and cuproptosis molecules (elesclomol‐copper, EsCu) for programming T cell infiltration is developed. The intravenously injected TUP accumulates at the tumor via the charge conversion of PH and hyperthermia effects of TUP. In metastatic clusters, ES and Cu, triggered by intracellular environments and hyperthermia, are readily released. ES and Cu simultaneously induce cuproptosis of cancer cells and stimulate immune responses. This process destroys self‐defense mechanisms and exacerbates cytotoxicity. The therapies facilitate the release of tumor‐associated antigens, including neoantigens and damage‐associated molecular patterns. Following this, the 3‐hydroxypyridin‐4‐one groups on TUP act as antigen reservoirs, transporting autologous tumor‐associated antigens to dendritic cells, thereby inducing prolonged immune activation. TUP acts as an antigen reservoir in copper apoptosis‐mediated lung metastasis, promoting the accumulation of immune cells in metastatic clusters and effectively preventing the progression of metastatic tumors.