Biomimetic mineralized nanocarriers based on reversal of cholesterol reprogramming against aggressive tumors by enhanced immunotherapy

The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism. Therefore, targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer. In this study, a nanosystem (AVA-COD@Fe) exhibiting dual enzymatic activity was developed through a biomimetic mineralization approach. Cholesterol oxidase (COD) facilitated the consumption of cholesterol, thereby impairing the migratory capacity of tumor cells and diminishing resilience on oxidative stress. Concurrently, COD catalyzed the production of hydrogen peroxide (H₂O₂), which compensated for inadequate levels of tumor cells, thereby enhancing ferroptosis and ultimately inhibiting tumor growth and metastasis. Meanwhile, as an immune sensitizer, avasimibe altered cholesterol distribution, and promoted the infiltration and vitality of cytotoxic T lymphocytes into tumors jointly with immunogenic cell death (ICD) induced by ferroptosis, and enhanced anti-tumor immunity. To elicit significant immune memory effects, this nanosystem was further combined with the anti-programmed cell death protein ligand-1 antibody, which effectively inhibited the growth of both primary and metastatic tumors, and demonstrated a robust systemic anti-tumor immune response. This study addressed modulation of tumor cell cholesterol metabolism as a strategic entry point for tumor suppression, significantly curtailing tumor progression, and activating systemic immune responses, thereby offering a new perspective for future cancer therapies.