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

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.