Reprogramming Macrophage Function via Cholesterol Modulation and Redox Signaling Using a Multifunctional Nanoplatform...

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. In vitro and in vivo 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.