DysUFMylation reprograms immunosuppressive neutrophils to potentiate anti-PD-1 therapy in hepatocellular carcinoma - PubMed
3 days ago
- #Tumor microenvironment
- #Immunotherapy
- #Hepatocellular carcinoma
- UFL1-mediated UFMylation is critical in remodeling the immune microenvironment of hepatocellular carcinoma (HCC).
- Low UFL1 expression enhances CD8+ T-cell infiltration and cytotoxicity while reducing tumor-associated neutrophil (TAN) infiltration and N2-like polarization.
- UFL1 deficiency impairs PRMT5 stability, inhibiting NF-κB p65 DNA binding and reducing CXCL8 expression, leading to decreased neutrophil infiltration and N2 polarization.
- Low UFL1 expression synergizes with anti-PD-1 therapy to prolong survival in HCC models.
- Pharmacologic inhibition of CXCL8-CXCR1/2 signaling with SX-682 mimics the effects of low UFL1 expression.
- Patients responding to immunotherapy show reduced UFL1, PRMT5, and CXCL8 expression, decreased neutrophil infiltration, elevated CD8+ T-cell activity, and lower serum CXCL8 levels.
- The UFL1-PRMT5-NF-κB p65-CXCL8 axis governs neutrophil-driven immunosuppression in HCC.
- CXCL8 is identified as a predictive biomarker and therapeutic target to optimize immunotherapy in HCC patients.