Targeting carbonic anhydrase IX/XII prevents the anti-ferroptotic effect of stromal lactic acid in prostate carcinoma

Ferroptosis is a form of regulated cell death dependent on iron-driven phospholipid peroxidation and is controlled by both cell autonomous and non-cell autonomous mechanisms. In prostate cancer (PCa), tumor cells engage in a metabolic crosstalk with cancer-associated fibroblasts (CAFs), resulting in increased utilization of CAF-secreted lactic acid, that ultimately supports cancer aggressiveness. In this context, the effect of the prostate tumor microenvironment in modulating ferroptosis sensitivity has not yet been extensively investigated. Here, we demonstrate that CAF-secreted lactic acid protects PCa cells from ferroptosis induction and supports the upregulation of the antioxidant enzyme glutathione peroxidase 4 (GPX4). Interestingly, targeting carbonic anhydrase IX/XII (CA IX/XII), the main regulators of microenvironmental acidosis, in tumor and stromal compartments hinders lactic acid shuttle within the tumor–stroma interplay and thus, prevents ferroptosis resistance induced by lactic acid. Analyses of tissue samples from PCa patients also revealed that GPX4, CA IX, and CA XII expression levels increase during PCa progression. Overall, these findings support a role for stromal lactic acid in mediating ferroptosis resistance in PCa, identifying CA IX/XII as potential therapeutic targets regulating ferroptosis sensitivity.