Druggable β-catenin palmitoyl-switch coordinates immune evasion via immunogenic ferroptosis resistance and PD-L1-mediated immunosuppression

T cells, thereby impairing both the initiation and effector phases of anti-tumor immunity. Clinically, ZDHHC5 expression predicts poor survival and resistance to anti-PD-L1 therapy. Silencing ZDHHC5 reduced tumor growth in patient-derived organoids and xenografts, while Zdhhc5 ablation in mice inhibited CRC progression by reversing immunogenic ferroptosis suppression and alleviating PD-L1-mediated T cell inhibition. Importantly, β-cat-oxazole, a first-in-class inhibitor, disrupts ZDHHC5-β-catenin binding, thereby restoring immunogenic ferroptosis and blocking PD-L1-mediated immunosuppression, ultimately suppressing tumor growth. Our findings establish targeting of this palmitoyl-switch as a precision strategy to overcome therapeutic resistance.