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

ST6GAL1 plays a critical role in tumor progression and immune regulation in colorectal cancer (CRC). Its depletion significantly suppresses the malignant phenotype of CRC cells and enhances the efficacy of anti‐PD‐L1 therapy. High ST6GAL1 expression promotes an immune‐activated tumor microenvironment (TME), characterized by increased infiltration of CD8+ T cells and M1 macrophages, thereby improving sensitivity to immunotherapy. Abstract 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. ST6GAL1 plays a critical role in tumor progression and immune regulation in colorectal cancer (CRC). Its depletion significantly suppresses the malignant phenotype of CRC cells and enhances the efficacy of anti-PD-L1 therapy. High ST6GAL1 expression promotes an immune-activated tumor microenvironment (TME), characterized by increased infiltration of CD8 + T cells and M1 macrophages, thereby improving sensitivity to immunotherapy. Abstract 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. Advanced Science, Volume 12, Issue 42, November 13, 2025.