Breaking the Lipid Bottleneck: A Mitophagy-Driven Nanoregulator Amplifies Ferroptosis for Colorectal Cancer Immunotherapy.

Abstract

Colorectal cancer (CRC) therapy is severely constrained by the immunosuppressive tumor microenvironment (TME). This study presents a TME-responsive nanometabolic regulator, ZnO2@Fe@HA (ZFH), designed to bridge mitochondrial dysfunction, lipid reprogramming, and ferroptosis to enhance anti-tumor immunity. ZFH specifically dissociates in the acidic TME, releasing Zn2 +, Fe2 +, and H2O2. Crucially, ZFH leverages Zn2 + to trigger mitochondrial oxidative stress and mitophagy, which subsequently disrupts the mitochondrial fatty acid β-oxidation pathway. This mitochondria-driven metabolic reprogramming causes a substantial accumulation of intracellular free fatty acids, effectively providing abundant lipid substrates to fuel iron-catalyzed lipid peroxidation. This cascade successfully overcomes the lipid deficiency bottleneck of conventional ferroptosis. The resulting intense ferroptosis induces potent immunogenic cell death (ICD), facilitating dendritic cell maturation and effector T cell infiltration. In vitro and in vivo results demonstrate that ZFH effectively suppresses CRC growth via this mitochondria-lipid-ferroptosis axis. This mechanism-guided strategy offers a promising paradigm for treating refractory CRC.