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.