Clinical Chemotherapeutic Agent Coordinated Copper‐Based Nanoadjuvants for Efficiently Sensitizing Cancer Chemo‐Immunotherapy by Cuproptosis‐Mediated Mitochondrial Metabolic Reprogramming

Abstract Chemo‐immunotherapy has shown great success in boosting systemic anti‐tumor effects in the clinic. However, cancer cells can escape the maximum impact of chemotherapy through intracellular symbiotic bacteria and abnormally activated macropinocytosis, while cancer immune evasion is largely facilitated by the programmed cell death 1 ligand 1 (PD‐L1) protein and tumor‐secreted exosomes. To efficiently sensitize chemo‐immunotherapy, the clinical mitoxantrone (MTO) is therefore rationally coordinated with Cu²⁺ to develop nanoscale metal‐organic frameworks (MTO‐Cu), then loaded with the macropinocytosis and exosome secretion inhibitor amiloride (AMI) and modified with targeted chondroitin sulfate (CS) to form CS/MTO‐Cu@AMI nanoadjuvant. Notably, the coordinated Cu²⁺ effectively triggers cuproptosis‐induced mitochondrial dysfunction, which activates AMPK pathway‐mediated PD‐L1 protein degradation, deprives energy supply for macropinocytosis and exosome release, and amplifies oxidative stress for deactivating intracellular bacteria, thus efficiently sensitizing chemo‐immunotherapy. Meanwhile, AMI suppresses macropinocytosis and exosome secretion to act synergistically with Cu²⁺‐caused chemo‐immunotherapy potentiation. Moreover, damaged dsDNA during CS/MTO‐Cu@AMI treatment activates the cGAS‐STING pathway, further evoking the anti‐tumor immunity. Additionally, the attached CS endows CS/MTO‐Cu@AMI with specific tumor targeting and hyaluronidase‐responsive charge reversal property, while MTO‐Cu endows this nanoadjuvant with pH/GSH dual‐responsive release behavior. Therefore, CS/MTO‐Cu@AMI efficiently sensitizes chemotherapy and activates systemic antitumor immunity in vitro and in vivo, providing an innovative solution to potentiate cancer chemo‐immunotherapy.