O-GlcNAcylated TCF4 Drives Ferroptosis Resistance and Tumor-Associated Macrophage Infiltration to Promote Colorectal Cancer Liver Metastasis

Abstract

Background: Colorectal cancer liver metastasis (CRLM) remains a major cause of mortality in colorectal cancer (CRC), while the upstream molecular mechanisms linking tumor cell adaptation and immune microenvironment remodeling remain poorly understood. Methods: By integrating single-cell RNA sequencing, multi-omics analysis, clinical cohorts, and functional experiments, we investigated the role and mechanism of TCF4 post-translational modification in CRLM progression. Results: We identified O-GlcNAcylated TCF4 as a critical driver of CRLM. TCF4 was significantly upregulated in CRLM and associated with poor prognosis. Mechanistically, OGT-mediated O-GlcNAcylation at Ser163 promoted TCF4 nuclear localization and enhanced its transcriptional activity. O-GlcNAcylated TCF4 directly activated GPX4 transcription, conferring ferroptosis resistance and preserving the malignant characteristics of CRC cells. Furthermore, TCF4 promoted CSF1 secretion, activating the CSF1/CSF1R axis to facilitate TAM recruitment and M2 macrophage polarization, thereby establishing an immunosuppressive metastatic niche. Conclusions: Our study reveals an O-GlcNAcylated TCF4–ferroptosis–immune regulatory axis that coordinates tumor intrinsic adaptation and microenvironmental remodeling during CRLM progression, providing potential therapeutic targets for preventing CRLM.