2. Academic Validation
  3. DysUFMylation reprograms immunosuppressive neutrophils to potentiate anti-PD-1 therapy in hepatocellular carcinoma

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

  • Cancer Lett. 2026 May 1:645:218395. doi: 10.1016/j.canlet.2026.218395.
Xukang Gao 1,  Min Xu 2,  Zeping Han 1,  Zhiqiu Hu 3,  Yipeng Su 1,  Guoqiang Sun 1,  Wei Chen 1,  Song Qiu 4,  Shuangjian Qiu 1,  Mien-Chie Hung 5,  Chenhao Zhou 6,  Yong Yi 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, PR China.
  • 2 Department of Thoracic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China.
  • 3 Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201100, PR China.
  • 4 Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, Shanghai, 200241, PR China.
  • 5 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan, 40402. Electronic address: [email protected].
  • 6 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, PR China. Electronic address: [email protected].
  • 7 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, PR China. Electronic address: [email protected].
PMID: 41780840 DOI: 10.1016/j.canlet.2026.218395
Abstract

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.

Keywords

Anti-PD-1 therapy; DysUFMylation; Hepatocellular carcinoma; Tumor immune microenvironment; Tumor-associated neutrophils.

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