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. Here, by analyzing clinical HCC specimens, we found that levels of ubiquitin-fold modifier 1 conjugation (UFMylation), a ubiquitin-like modification, correlated with prognosis, pathological 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 TEAD4 to upregulate poliovirus receptor (PVR), enabling natural killer (NK) cell evasion via the PVR-TIGIT axis. Reduced UFMylation accelerated metastasis in models of HCC, as well as colorectal cancer (CRC), while EMD restoration mitigated these effects. Combined PD-1 and TIGIT blockade significantly suppressed tumor growth and metastasis in UFMylation-deficient settings. Together, these data suggest that UFMylation suppresses HCC and CRC 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.