A synergistic cascade nanoreactor breaks bladder cancer chemoresistance: Synergizing cholesterol metabolism reprogramming with cGAS-STING-mediated metallotherapy

Abstract

Bladder cancer chemoresistance arises from a self-reinforcing vicious cycle of aberrant cholesterol metabolism and immunosuppression, which conventional single-target therapies fail to disrupt. Here, we report a folate-targeted zeolitic imidazolate framework-67 (ZIF67)-based nanoreactor termed CCZF, co-loaded with cholesterol 25-hydroxylase (CH25H) and cisplatin, to orchestrate a metabolism-chemo-immunity cascade with mutually amplifying components. First, the intrinsic catalase (CAT)-like activity of ZIF67 generates oxygen in situ to fuel CH25H-mediated cholesterol depletion that reaches 72% in resistant bladder cancer cells. This process disrupts lipid raft structure and downregulates P-glycoprotein (P-gp), resulting in 97.2% cisplatin retention in resistant cells. Second, enhanced cisplatin cytotoxicity induces nucleocytoplasmic translocation of high-mobility group box 1 (HMGB1), an early molecular signature associated with immunogenic cell death (ICD). Third, Co2+ released from degraded ZIF67 activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. The CH25H-derived metabolite 25-hydroxycholesterol (25HC) acts as an immunomodulatory oxysterol that works with high-mobility group box 1 (HMGB1) to potentiate toll-like receptor 4 (TLR4)-associated innate immune signaling and remodel the immunosuppressive tumor microenvironment. In MB49R tumor-bearing mice, intratumoral CD8+ T cell infiltration increases by 2.3-fold on day 14 after treatment. In preclinical bladder cancer models, this tripartite synergy achieves 95.9% short-term tumor growth suppression with no obvious systemic toxicity under the tested dosage and observation period, providing a promising multifaceted strategy for treating chemo-resistant bladder cancer.