Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer

Lipid peroxidation–dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3…