Abstract
The SFMBT2 protein is a Polycomb group protein implicated in transcriptional regulation and cancer biology. Here, we investigated the role of SFMBT2 promoter hypermethylation in colorectal cancer (CRC) development and its clinical relevance. Using CRC cell lines, FFPE tissues, plasma samples, and public datasets, we show that promoter hypermethylation is associated with the transcriptional silencing of SFMBT2. SFMBT2 expression was high in normal intestinal mucosa but progressively reduced in advanced adenoma, primary CRC, and metastatic lesions, accompanied by increased promoter methylation. Elevated plasma SFMBT2 methylation was associated with higher recurrence risk in stage III CRC and poor prognosis in stage IV disease. Bioinformatic analyses further linked high SFMBT2 expression to enhanced immune cell infiltration and activation of immune-related pathways. These findings identify SFMBT2 hypermethylation as a potential noninvasive biomarker for recurrence risk stratification and prognostic assessment in advanced CRC, and suggest a role for SFMBT2 in shaping the tumor immune microenvironment.