Copper Depletion Nanoparticles Potentiate Cancer Immunotherapy by Avoiding Innate and Adaptive Immune Resistance

ABSTRACT Currently, cluster of differentiation 47 (CD47) and programmed death ligand 1 (PD‐L1) targeted bispecific antibodies have been widely studied in clinical trials to overcome innate and adaptive immune resistance simultaneously. However, the excessive immune‐related adverse events caused by the on‐target off‐tumor immune‐toxicity cast a shadow over their future clinical usage. Thus, how to safely, effectively, and selectively regulate CD47 and PD‐L1 in tumors at the same time is still a difficult issue to solve. Here, we developed a mitochondria‐targeted copper‐withdrawal nanoparticle CYN‐CDA@Alb to more efficaciously depress CD47 and PD‐L1 expression (only 1/50 dosage of common copper chelators), on account of the depression of mitochondria/Adenosine 5’‐monophosphate‐activated protein kinase (AMPK)/c‐MYC signal pathway. By doing this, CYN‐CDA@Alb reverses immune resistance by increasing T cell killing capacity and macrophage phagocytosis ability to tumor cells, leading to the following depressed tumor metastasis and slowed tumor growth. Moreover, CYN‐CDA@Alb also avoids the usually increased innate and adaptive immune resistance after radiotherapy by depressing CD47 and PD‐L1. Our findings altogether suggest the potential usage of copper ion‐depleting nanoparticles as substitutes for CD47/PD‐L1 bispecific antibodies to simultaneously overcome innate and adaptive immune‐resistance.