FAT4 overexpression promotes antitumor immunity by regulating the beta-catenin/STT3/PD-L1 axis in cervical cancer

Background FAT4 (FAT Atypical Cadherin 4) is a member of the cadherin-associated protein family, which has been shown to function as a tumor suppressor by inhibiting proliferation and metastasis. The Wnt/beta-catenin pathway activation is highly associated with PD-L1-associated tumor immune escape. Here, we report the mechanism by which FAT4 overexpression regulates anti-tumor immunity in cervical cancer by inhibiting PD-L1 N-glycosylation and cell membrane localization in a beta-catenin-dependent manner.Methods FAT4 expression was first detected in cervical cancer tissues and cell lines. Cell proliferation, clone formation, and immunofluorescence were used to determine the tumor suppressive impact of FAT4 overexpression in vitro, and the findings were confirmed in immunodeficient and immunocomplete mice xenografts. Through functional and mechanistic experiments in vivo and in vitro, we investigated how FAT4 overexpression affects the antitumor immunity via the beta-catenin/STT3/PD-L1 axis.Results FAT4 is downregulated in cervical cancer tissues and cell lines. We determined that FAT4 binds to beta-catenin and antagonizes its nuclear localization, promotes phosphorylation and degradation of beta-catenin by the degradation complexes (AXIN1, APC, GSK3 beta, CK1). FAT4 overexpression decreases programmed death-ligand 1 (PD-L1) mRNA expression at the transcriptional level, and causes aberrant glycosylation of PD-L1 via STT3A at the post-translational modifications (PTMs) level, leading to its endoplasmic reticulum (ER) accumulation and polyubiquitination-dependent degradation. We found that FAT4 overexpression promotes aberrant PD-L1 glycosylation and degradation in a beta-catenin-dependent manner, thereby increasing cytotoxic T lymphocyte (CTL) activity in immunoreactive mouse models.Conclusions These findings address the basis of Wnt/beta-catenin pathway activation in cervical cancer and provide combination immunotherapy options for targeting the FAT4/beta-catenin/STT3/PD-L1 axis.