Rewiring cholesterol vulnerabilities with biomaterials: Mechanisms and opportunities for cancer therapy

Tumor progression is accompanied by adaptive metabolic rewiring that extends beyond energy and amino acid metabolism to lipid networks. Among these alterations, disrupted cholesterol homeostasis has emerged as a key driver of tumor proliferation, migration, invasion, chemoresistance and immune escape. Cholesterol metabolism also shapes immune cell function, thereby linking tumor-intrinsic metabolic adaptation to immune remodeling in the tumor microenvironment. Recent advances in biomaterial-based therapeutics have expanded the scope of cholesterol-targeted cancer therapy. This Review summarizes how engineered biomaterials regulate cholesterol supply and uptake, intracellular cholesterol trafficking, membrane organization and cholesterol oxidation, and how these strategies reshape tumor cell survival, therapeutic resistance and antitumor immunity. We further discuss the integration of cholesterol-targeted biomaterials with chemotherapy, photodynamic therapy, sonodynamic therapy and immunotherapy, as well as key translational challenges, including metabolic compensation, preservation of cholesterol balance in normal tissues, the context-dependent biological effects of sterol products and the need for product-resolved analysis, since changes in total cholesterol or ROS alone cannot establish their identity or activity, and therapeutic heterogeneity across cholesterol-dependent tumor phenotypes. Biomaterials that target cholesterol metabolism offer a promising route to overcome therapy resistance and improve combination immunotherapy, but their clinical translation will require precise definition of responsive tumor types, target cell populations and actionable metabolic vulnerabilities.