Reprogramming Macrophage Function via Cholesterol Modulation and Redox Signaling Using a Multifunctional Nanoplatform for Postoperative Breast Cancer Management.

Abstract

Postoperative recurrence and infection remain major obstacles to effective breast cancer recovery, often driven by cholesterol-mediated macrophage dysfunction. Here, we report the development of CuMPmC, a multifunctional nanoplatform constructed through copper-dopamine chelation and self-polymerization, functionalized with mannose for selective targeting of M2-like macrophages, and loaded with cholesterol oxidase (ChOx). CuMPmC depletes macrophage membrane cholesterol via ChOx-mediated oxidation, enhancing plasma membrane fluidity and thereby promoting macrophage chemotaxis. Simultaneously, ChOx-generated H₂O₂ drives copper-mediated Fenton-like reactions to generate moderate reactive oxygen species, while depleting glutathione within the tumor microenvironment. This dual action polarizes macrophages toward a proinflammatory M1 phenotype, enhancing clearance of tumor cells and pathogens. Copper ions further potentiate ChOx enzymatic activity and stimulate angiogenesis. <i>In vitro</i> and <i>in vivo</i> analyses, including transcriptomic profiling, demonstrate that CuMPmC enhances macrophage migration and phagocytic capacity through coordinated cholesterol modulation and ROS-driven signaling. Treatment with CuMPmC reduced postoperative tumor recurrence and infection in murine models. These findings highlight the pivotal role of cholesterol metabolism in reprogramming macrophage function and offer a promising immunotherapeutic strategy for postoperative breast cancer management.