Endothelial Fat4 regulates tumor angiogenesis and tumor immunity

The atypical cadherin FAT4 has mainly been studied as a tumor suppressor, but a pan-cancer analysis of its expression in human tumors suggests this view is likely oversimplified. Here, we identify that across multiple cancer types, FAT4 expression was enriched in cancer patients with high angiogenic activity and low T-cell immunity signatures and was predominantly observed in tumor endothelial cells. Consistently, endothelial Fat4 is required for both retinal and tumor angiogenesis in preclinical mouse models. Mechanistically, FAT4 governs endothelial planar cell polarity (PCP), which is essential for coordinated sprouting and vessel patterning. Strikingly, loss of endothelial FAT4 normalizes tumor vessels, enhances tumor immunity and responsiveness to immune checkpoint blockade, suggesting that targeting FAT4 can overcome endothelial cell anergy and restore anti-tumor immunity. These findings reposition FAT4 as a regulator that links angiogenesis to tumor immunity and extend its function beyond a tumor-cell-intrinsic suppressor. Targeting this pathway may offer an opportunity to normalize tumor vasculature and enhance immunotherapy, but its clinical success will hinge on recognizing the distinct and context-dependent roles of FAT4 in tumor cells and within the tumor microenvironment. Overall design: RNA sequencing of wild type mouse cardiac endothelial cells and their Fat4 knockdown (ShFat4) cells.