ST6GAL1‐Mediated Sialylation Stabilizes PD‐L1 and Drives Immunosuppressive Tumor Microenvironment in Colorectal Cancer

Abnormal glycogene expression is a recognized cancer hallmark, but its impact on the colorectal cancer (CRC) tumor microenvironment (TME) remains unclear. Utilizing bioinformatics analysis on TCGA and GEO datasets, a seven-glycogene signature is identified for precise glycogene-based classification in CRC. ST6GAL1, a key focus, emerges as a significant predictor of poor prognosis, with its upregulation linked to unfavorable outcomes in CRC. Functional experiments demonstrate that loss of ST6GAL1 inhibits CRC proliferation, migration, invasion, and metastasis. ST6GAL1-mediated sialylation of PD-L1 is critical for maintaining its stability in colorectal cancer cells, and ST6GAL1 knockdown leads to reduced protein stability and increased ubiquitination. ST6GAL1 knockdown in MC38 tumor-bearing mice enhances the antitumor effect of anti-PD-L1 therapy, resulting in smaller tumor sizes and reduced tumor volume compared to control groups. Single-cell analysis reveals ST6GAL1's influence on immune cell composition in the TME, particularly affecting CD8⁺ T cells. Taken together, ST6GAL1 is confirmed to act as an important regulating factor in CRC development through immune response and TME composition and has the potential to serve as a novel biomarker in CRC treatment.