Phase Separation of ZBED2 Stabilizes ILK to Drive Metastasis and Immune Evasion in Esophageal Squamous Cell Carcinoma

Abstract Metastasis remains a leading cause of mortality in patients with esophageal squamous cell carcinoma (ESCC), underscoring the urgent need to elucidate the molecular mechanisms driving disease progression. In this study, we delineated that zinc finger BED-type containing 2 (ZBED2), a zinc finger protein, correlates with inferior survival outcomes and metastasis in patients with ESCC. ZBED2 formed phase-separated nuclear condensates that functionally promote tumor metastasis, and integrin-linked kinase (ILK) was pinpointed as a critical downstream effector in mediating the prometastatic function of ZBED2. Mechanistically, ZBED2 enhanced the transcription of HSP90AA1, promoted the physical interaction between HSP90AA1 and ILK, and consequently stabilized ILK by suppressing its ubiquitination. Subsequently, ILK promoted PD-L1 transcription and CD8+ T-cell exhaustion, thereby creating an immunosuppressive microenvironment that facilitates cancer metastasis. Collectively, these findings establish the pivotal role of ZBED2 in driving ESCC metastasis and immune evasion, thereby validating it as a promising therapeutic target for this aggressive malignancy. Significance: A ZBED2-HSP90AA1-ILK-PD-L1 regulatory axis drives esophageal squamous cell carcinoma metastasis and immune evasion, identifying targeting ZBED2 as a potential therapeutic strategy for improving the prognosis of patients.