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

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.