FGFR4 suppresses antitumor immunity and cuproptosis by disrupting CYLD-mediated stabilization of STING and FDX1.

The fibroblast growth factor receptor (FGFR) pathway is frequently dysregulated in cancer and contributes to tumor progression and immune evasion; however, the underlying immunosuppressive mechanisms remain incompletely understood. Here, we identify FGFR4 as a key FGFR family member that suppresses antitumor immunity. Mechanistically, FGFR4 promotes GRB2-dependent phosphorylation and inactivation of the deubiquitinase CYLD, leading to ubiquitin-proteasome-mediated degradation of STING and FDX1. Loss of STING attenuates type I interferon signaling and impairs cytotoxic immune responses, while destabilization of FDX1 diminishes sensitivity to cuproptosis. Inhibition of FGFR4 restores CYLD activity, stabilizes STING and FDX1, and enhances responsiveness to the STING agonist diABZI. Notably, CYLD-dependent stabilization of FDX1 potentiates elesclomol-induced cuproptosis, triggering mitochondrial stress and cytosolic mtDNA release, thereby activating the cGAS-STING pathway and amplifying STING-dependent immune signaling. Combination therapy with lenvatinib and elesclomol synergistically suppressed tumor growth in immunocompetent mouse models. Across patient cohorts, FGFR4-high/STING-low tumors were associated with inferior responses to anti-PD-1-based therapy. Together, these findings establish FGFR4 as a central regulator of antitumor immunity and cuproptosis and highlight combined FGFR4 inhibition and cuproptosis induction as a promising therapeutic strategy.