FAT4 restrains epithelial-mesenchymal transition and metastasis in cervical cancer and shapes the tumor immune microenvironment

Metastatic dissemination remains the major cause of mortality in cervical cancer. FAT4, an atypical cadherin upstream of Hippo signaling, has been implicated in tumor suppression, yet its clinical relevance and mechanistic role in cervical cancer metastasis are insufficiently defined. We assessed FAT4 expression by immunohistochemistry in 40 paired cervical cancer and adjacent tissues and analyzed clinicopathological associations. The immune landscape of 10 freshly resected tumors was profiled using mass cytometry (CyTOF). To interrogate causality, we activated endogenous FAT4 using CRISPR activation (dCas9-SAM) in cervical cancer cell lines, followed by migration/invasion assays and EMT marker analyses. Metastatic potential was evaluated in xenograft and syngeneic mouse models. FAT4 expression was reduced in tumors compared with matched non-tumor tissues and aligned with metastatic features. CyTOF delineated distinct immune compositions between FAT4-high and FAT4-low tumors, indicating a remodeled tumor immune microenvironment. CRISPRa-mediated FAT4 activation curtailed cell migration and invasion, restored epithelial markers, and suppressed mesenchymal markers, consistent with epithelial-mesenchymal transition (EMT) restraint. In vivo, enforced FAT4 reduced metastatic burden. Mechanistically, FAT4 activation was associated with suppression of EMT transcriptional programs and with signaling signatures consistent with reduced YAP/TAZ activity. FAT4 acts as a metastasis suppressor in cervical cancer by constraining EMT and remodeling the tumor immune microenvironment. These data support FAT4 as a potential biomarker and therapeutic entry point for metastasis control. FAT4 is frequently downregulated in cervical cancer and is associated with aggressive clinicopathologic features. FAT4 activation reverses epithelial–mesenchymal transition and suppresses cervical cancer cell migration and invasion in vitro. FAT4 activation reduces metastatic burden, restrains tumor progression, and prolongs survival in mouse models. FAT4-high tumors exhibit a lymphocyte-enriched, less CAF-dominant microenvironment and support the biomarker potential of FAT4 in cervical cancer.