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

Immune evasion remains a major challenge in colorectal cancer (CRC) treatment. Here, we identify that druggable β-catenin palmitoylation at cysteine 466 (C466) by ZDHHC5 acts as a competitive switch, displacing S-nitrosylation and coordinating an immunosuppressive program. The palmitoylated state stabilizes the β-catenin/TCF4 complex, which simultaneously upregulates SLC7A11 to suppress immunogenic ferroptosis, critical for CD8+ T cell priming, and PD-L1 to inhibit cytotoxic CD8+ 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.