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

Area of Science:

• Nanomedicine
• Immunotherapy
• Cancer Research

Background:

• Bispecific antibodies targeting CD47 and PD-L1 aim to overcome immune resistance but cause significant on-target, off-tumor toxicities.
• Simultaneous and selective regulation of CD47 and PD-L1 in tumors remains a clinical challenge.
• Radiotherapy can paradoxically increase innate and adaptive immune resistance by upregulating CD47 and PD-L1.

Purpose of the Study:

• To develop a novel nanoparticle-based strategy for simultaneous and safe downregulation of tumor CD47 and PD-L1.
• To investigate the efficacy of mitochondria-targeted copper-withdrawal nanoparticles (CYN-CDA@Alb) in reversing immune resistance.
• To evaluate the potential of CYN-CDA@Alb as an alternative to CD47/PD-L1 bispecific antibodies.

Main Methods:

• Development of mitochondria-targeted copper-withdrawal nanoparticles (CYN-CDA@Alb).
• Assessment of CYN-CDA@Alb's effect on CD47 and PD-L1 expression via the mitochondria/AMPK/c-MYC pathway.
• Evaluation of CYN-CDA@Alb's impact on T cell killing, macrophage phagocytosis, tumor metastasis, and tumor growth, including post-radiotherapy effects.

Main Results:

• CYN-CDA@Alb significantly downregulated CD47 and PD-L1 expression at a 50-fold lower dosage compared to common copper chelators.
• The nanoparticles reversed immune resistance by enhancing T cell cytotoxicity and macrophage phagocytosis, leading to reduced tumor metastasis and growth.
• CYN-CDA@Alb mitigated the immune resistance often induced by radiotherapy by suppressing CD47 and PD-L1.

Conclusions:

• Mitochondria-targeted copper-withdrawal nanoparticles offer a safe and effective method for simultaneous CD47 and PD-L1 downregulation in tumors.
• CYN-CDA@Alb demonstrates potential as a superior alternative to CD47/PD-L1 bispecific antibodies, overcoming immune resistance with reduced toxicity.
• Copper ion-depleting nanoparticles represent a promising strategy for enhancing cancer immunotherapy and overcoming treatment resistance.