Materials‐Guided Gene‐Ionizable Lipid Nanoparticles to Reverse Iron‐Associated Immune Resistance in Renal Cancer

ABSTRACT Iron overload is a common metabolic disturbance in cancer and contributes to poor outcomes in renal cell carcinoma (RCC), yet its effects on the tumour immune microenvironment remain unclear. Here we identify a previously unrecognized immunosuppressive axis in which iron overload downregulates the palmitoyltransferase ZDHHC12 in CD8 ⁺ T cells, leading to impaired palmitoylation of the mitochondrial protein FDX1. This stabilizes FDX1 and drives cuproptosis, a recently described copper‐dependent cell death pathway, thereby compromising T cell effector function and diminishing responses to immune checkpoint blockade. To restore T cell activity, we engineered lipid nanoparticles (ZDHHC12‐LNPs) for the delivery of Zdhhc12. These nanoparticles exhibited optimal physicochemical properties, efficiently restored FDX1 palmitoylation, rescued CD8 ⁺ T cell function, and synergized with PD‐1 blockade in preclinical RCC models without inducing systemic toxicity. Our findings uncover the iron‐ZDHHC12‐FDX1 axis as a metabolic checkpoint of T cell immunity and demonstrate a nanotechnology‐based strategy to overcome iron‐driven immunosuppression, offering translational potential for patients with iron‐overloaded RCC.