UFMylation Suppresses Hepatocellular Carcinoma Metastasis by Inhibiting β-Catenin-Driven Hybrid EMT and NK Cell Evasion

  • Cancer Res. 2026 Jul 2;86(13):3213-3232. doi: 10.1158/0008-5472.CAN-25-4755.
Min Xu  1 ,  Xukang Gao  2 ,  Jie Zhao  3 ,  Dongwei Xu  3  4 ,  Chenchao Ma  1  5 ,  Mingming Fan  6 ,  Jianbo Lin  7 ,  Xiaoni Kong  8 ,  Zhicong Zhao  3 ,  Meng Li  3 ,  Shaoqing Liu  9  10
Affiliations
  • 1. Department of Thoracic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.
  • 2. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
  • 3. Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
  • 4. Shanghai Immune Therapy Institute, Shanghai, P.R. China.
  • 5. Department of Thoracic Surgery, Tongji University Affiliated Shanghai Pulmonary Hospital, Shanghai, P.R. China.
  • 6. Hepatic Surgery IV, The Third Affiliated Hospital of Naval Medical University, Shanghai, P.R. China.
  • 7. Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.
  • 8. Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
  • 9. Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China.
  • 10. Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China.
PMID: 41996487 DOI: 10.1158/0008-5472.CAN-25-4755
Abstract

Hepatocellular carcinoma (HCC) is a deadly malignancy marked by frequent metastasis and recurrence. Despite therapeutic advances, HCC metastasis and immune evasion remain major hurdles to effective treatment. In this study, by analyzing clinical HCC specimens, we found that levels of ubiquitin-fold modifier 1 conjugation (UFMylation), a ubiquitin-like modification, correlated with prognosis, pathologic features, and metastatic burden. Emerin (EMD), a nuclear envelope protein, was identified as a UFMylation substrate. Loss of UFMylation destabilized EMD via proteasomal degradation, promoting nuclear β-catenin accumulation and hybrid epithelial-mesenchymal transition (EMT), enhancing tumor cell migration, invasion, circulating tumor cell formation, and extravasation. Nuclear β-catenin also interacted with TEA domain transcription factor 4 to upregulate poliovirus receptor (PVR), enabling natural killer (NK) cell evasion via the PVR-T-cell immunoglobulin and ITIM domain (TIGIT) axis. Reduced UFMylation accelerated metastasis in models of HCC, as well as colorectal Cancer, whereas EMD restoration mitigated these effects. Combined programmed cell death protein 1 and TIGIT blockade significantly suppressed tumor growth and metastasis in UFMylation-deficient settings. Together, these data suggest that UFMylation suppresses HCC and colorectal Cancer metastasis by stabilizing EMD, thereby inhibiting β-catenin-driven hybrid EMT and PVR-mediated immune evasion. These preclinical findings suggest that activating the UFMylation axis may have therapeutic potential for metastatic HCC.

Significance: UFMylation-mediated stabilization of EMD inhibits β-catenin activity to prevent hybrid EMT and PVR/TIGIT-mediated immune evasion, which suppresses hepatocellular carcinoma progression and can be harnessed to target metastatic liver Cancer.

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