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, ZnO 2 @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 Zn 2 + , Fe 2 + , and H 2 O 2 . Crucially, ZFH leverages Zn 2 + 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.