Cu2+-Coordinated NLG919: A Drug Delivery Nanoplatform to Activate Antitumor Immunity via Inducing Immunogenic Cell Death and Inhibiting Indoleamine 2,3-Dioxygenase-1

Chemotherapeutic drug combination to activate systemic antitumor immunity is appealing to fight metastatic tumors. In this study, copper ion (Cu²⁺) is able to coordinate with NLG919, serving as a nanoplatform (designated as CuN) for drug delivery. Meanwhile, such a metal-coordinated nanomedicine can also activate systemic antitumor immunity through immunogenic cell death (ICD) induction and indoleamine 2,3-dioxygenase-1 (IDO1) inhibition. Some representing antitumor agents, including cinnamic acid, mitoxantrone, docetaxel, β-lapachone, tazemetostat and mocetinostat, can be encapsulated into CuN regardless of their different physicochemical characteristics. Taking β-lapachone for example, the drug-carrying CuN (designated as Lap@CuN) can catalyze the production of excessive reactive oxygen species (ROS) to suppress tumor cell proliferation and trigger a robust ICD to release damage associated molecular patterns (DAMPs). Consequently, Lap@CuN not only inhibits primary tumor growth through chemotherapy but also reactivates the immune cells to exert an abscopal effect. Benefiting from the immune modulatory effect, Lap@CuN reduces the lung metastasis while not causing obvious side effects on mice. This study presents a universal metal-coordinated nanoplatform for the delivery of chemotherapeutic combinations, offering new insights into the design of combination therapies that can potentiate immunotherapeutic responses.