DysUFMylation reprograms immunosuppressive neutrophils to potentiate anti-PD-1 therapy in hepatocellular carcinoma.

Immune checkpoint blockade has been used to treat transformed hepatocellular carcinoma (HCC), but its clinical benefit remains limited, underscoring the need to elucidate the underlying mechanisms of resistance and predictive biomarkers. Here, we identified that UFL1-mediated UFMylation plays a critical role in remodeling the immune microenvironment of HCC. Low UFL1 expression enhanced CD8+ T-cell infiltration and cytotoxicity while reducing tumor-associated neutrophil (TAN) infiltration and N2-like polarization, which correlated with an improved immunotherapy response. Mechanistically, UFL1 deficiency impaired the stability of PRMT5, thus inhibiting the DNA binding ability of NF-κB p65 and reducing the expression of CXCL8. This led to decreased neutrophil infiltration and N2 polarization, ultimately enhancing the CD8+ T-cell-mediated immune response. Low UFL1 expression synergized with anti-PD-1 therapy to prolong survival in orthotopic and spontaneous HCC models, whereas pharmacologic inhibition of CXCL8-CXCR1/2 signaling using SX-682 recapitulated these effects. Clinically, patients who responded to immunotherapy exhibited reduced UFL1, PRMT5 and CXCL8 expression; decreased neutrophil infiltration; elevated CD8+ T-cell activity; and lower serum CXCL8 levels. These findings reveal a UFL1-PRMT5-NF-κB p65-CXCL8 axis that governs neutrophil-driven immunosuppression and identify CXCL8 as both a predictive biomarker and therapeutic target to optimize immunotherapy in patients with HCC.