Cholesterol-depleting nanozyme amplifies membrane-diffusive ferroptosis for potentiating anti-tumor immunity in colorectal cancer.

To overcome limitations of conventional therapies and low immunotherapy response in colorectal cancer, we developed a cholesterol-depleting nanozyme (ChOx@Fe@C-MOF). This platform synergistically induces ferroptosis and anti-tumor immunity by integrating cholesterol oxidase (ChOx) with a carbonized MIL-100(Fe) carrier (Fe@C-MOF). ChOx disrupts tumor membrane lipid rafts to downregulate GPX4 and generate H₂O₂, while Fe@C-MOF catalyzes ROS production and glutathione depletion. In vitro, ChOx@Fe@C-MOF triggered robust lipid peroxidation, immunogenic cell death, and tumor growth suppression in CT26 models. It enhanced dendritic cell maturation, CD8⁺ T-cell infiltration, and cytokine production, converting immunosuppressive "cold" tumors into immunologically "hot" microenvironments. This strategy integrates cholesterol metabolism intervention with nanozyme catalysis for synergistic ferroptosis-immunotherapy.