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

Abstract 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 Cu 2 ⁺. The liberated Cu 2 ⁺ 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 H 2 O 2 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.