A Functional Nanocomposite Tri‐Activates Cuproptosis, Ferroptosis, and Mitophagy Death Pathway to Oppose Malignancies

Metal ion dyshomeostasis represents a therapeutic vulnerability in cancer, yet simultaneous targeting of multiple metal-dependent death pathways remains challenging. Herein, a pH-responsive copper-based metal-organic framework nanoplatform (Cu-MOF@DPCPX) is engineered to co-trigger cuproptosis, ferroptosis, and mitophagy through tumor-specific copper overload. The system leverages acidic tumor microenvironments for targeted degradation, releasing Cu²⁺. The liberated Cu²⁺ depletes overexpressed glutathione (GSH) to disrupt redox homeostasis and generates toxic Cu⁺ that initiates dual catalytic cycles. 1) Cu⁺ accumulation promotes lipoylated protein aggregation and Fe-S cluster loss, driving cuproptosis; 2) Cu⁺-mediated Fenton-like reactions convert endogenous H₂O₂ into hydroxyl radicals (·OH) and downregulate GPX4 to induce ferroptosis. Crucially, mitochondrial damage from these pathways activates mitophagy, which releases sequestered copper to establish a self-amplifying death cascade. In vivo, Cu-MOF@DPCPX demonstrates potent tumor suppression across multiple tumor models (4T1-breast, LLC-lung, PAN02-pancreatic, GL261-glioblastoma), while reprogramming immunosuppressive microenvironments via increased CD8⁺ T-cell infiltration and M1 macrophage polarization. This triple-pathway activation strategy overcomes monotherapy limitations and establishes a paradigm for metal-ion-based multimodal oncotherapy.