Boosting ubiquitin-proteasome system-mediated androgen receptor degradation and cGAS-STING pathway activation for synergistic prostate cancer therapy by engineered zinc-manganese oxide nanoparticles

Abstract

Androgen receptor (AR) is an essential target for prostate cancer (PCa) therapy, while required resistance due to AR overexpression/abnormal splicing often leads to therapeutic failure, and how to realize the synergistic therapeutic efficacy for PCa remains a challenge. Herein, a novel paradigm of zinc-manganese oxide nanoparticles (ZMONPs) is rationally engineered, which can cooperate in promoting ubiquitin-proteasome system (UPS)-mediated AR degradation and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway activation, thereby generating a tumoricidal immune microenvironment to elicit PCa cell death. Upon lysosomal acidolysis, ZMONPs promote zinc ions overload to produce more reactive oxygen species (ROS), which ultimately contribute to UPS-mediated AR degradation and tumoricidal effect. In PCa mouse models, ZMONPs significantly down-regulate the abundance of AR within the tumor microenvironment, further facilitating cGAS-STING signaling pathway activation to secrete C-C motif chemokine ligand 5 (CCL5) and interferon beta (IFN-β), which enhance dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration, thus realizing tumor growth inhibition in a cooperative manner. In addition, co-administration of ZMONPs and docetaxel presents notably synergistic therapeutic efficacy. Collectively, this study highlights the favorable effects of ZMONPs on AR degradation-related hormonal therapy and anti-tumor immunity, which may serve as a promising therapeutic strategy for PCa.