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

Metastasis remains a leading cause of mortality in esophageal squamous cell carcinoma (ESCC) patients, underscoring the urgent need to elucidate the molecular mechanisms driving disease progression. In this study, we delineated that ZBED2, a zinc finger protein, correlates with inferior survival outcomes and metastasis in ESCC patients. 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 pro-metastatic 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.