The Zeb1/system Xc- axis safeguards iron-loaded cancer-associated fibroblasts against ferroptosis and promotes immunosuppression in prostate cancer.

A subset of iron-loaded cancer-associated fibroblasts is unraveled in the tumor microenvironment of prostate cancer (PCa) and termed as the ferrum iron CAFs (FerroCAFs) in our previous study. Importantly, FerroCAFs have been identified as a source of C-C motif ligand 2 (CCL2), C-X-C motif ligand chemokines 1/2 (CXCL1/2), and colony-stimulating factor 1 (CSF1) to induce immunosuppression. However, the iron-loaded phenotype of FerroCAFs also elicits high amounts of lethal oxygen radicals, lipid peroxides and reactive oxygen species (ROS) due to iron excess. Consequently, the mechanism by which FerroCAFs resist ferroptosis, a form of cell death induced by iron-dependent lipid peroxidation, remains to be elucidated. Here, we find that the upregulation of cystine/glutamate antiporter System Xc-, specifically Slc7a11, functions as a protective mechanism that preserves FerroCAFs against ferroptosis. The zinc finger E-box binding homeobox 1 (Zeb1) occupies the Slc7a11 gene promoter region and activates Slc7a11 transcription. Knockdown of FerroCAF-specific Slc7a11 suppresses tumor growth and subverts immunosuppression. Collectively, this study demonstrates that Zeb1/System Xc- axis protects FerroCAFs against ferroptosis. Targeting this vulnerability of FerroCAFs by blockade of Zeb1/System Xc- axis provokes anti-tumor immunity in PCa, implying a promising CAF-centric immunotherapeutic strategy.