A self-amplifying cuproptosis nanomedicine to overcome immunosuppression by blocking tumor-derived exosomes for enhancing lung cancer immunotherapy

Lung cancer immunotherapy remains limited by the immunosuppressive tumor microenvironment (TME) and insufficient immunogenicity. Accumulating evidence indicates that tumor-derived exosomes (TDEs) play a pivotal role in shaping the immunosuppressive TME. Consequently, therapeutic strategies targeting TDE biogenesis and secretion offer a promising strategy to counteract tumor immune evasion. To this end, we developed an adenosine triphosphate (ATP)-responsive zeolitic imidazole framework-90 (ZIF-90)-based nanoplatform for the co-delivery of the exosome biosynthesis inhibitor GW4869 and the copper ionophore elesclomol (ES-Cu, a cuproptosis inducer). GW4869-mediated TDEs suppression alleviated immunosuppression and enhanced T-cell infiltration while simultaneously inducing reactive oxygen species (ROS) production to deplete glutathione (GSH). This GSH depletion potentiated ES-Cu-induced cuproptosis, and in combination with TDEs inhibition-mediated immunostimulation, established a positive feedback loop that remodels the TME to enhance antitumor immune responses. To our knowledge, this biomimetic nanoplatform presents an unexplored integration of exosome blockade with cuproptosis induction, establishing a novel paradigm for cancer immunotherapy.