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

ABSTRACT Chemotherapeutic drug combination to activate systemic antitumor immunity is appealing to fight metastatic tumors. In this study, copper ion (Cu 2+ ) 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.