ArticleCancer research2023
BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- The dual immune landscape of homologous recombination-deficient tumors: mechanisms and therapeutic implications.Cancer metastasis reviews · 2026Review
- Metabolic licensing of quiescent glioblastoma activation and immune evasion via astrocyte-mitochondria shuttle.Nature communications · 2026Article
- ST3Gal1 modulates intestinal barrier function and impacts human ulcerative colitis.Molecular medicine reports · 2026Article
- Investigating the utilization mechanism and kinetics of sialic acid mimetics in mammalian cell lines.RSC chemical biology · 2026Article
- Sialylation in Thyroid Carcinoma: An Overview of Mechanisms, Markers, and Therapeutic Opportunities.Journal of Cancer · 2026Review
- Polysialylation of Glioblastoma Cells Is Regulated by Autophagy Under Nutrient Deprivation.International journal of molecular sciences · 2025Article
- Sialic acid metabolism-based classification reveals novel metabolic subtypes with distinct characteristics of tumor microenvironment and clinical outcomes in gastric cancer.Cancer cell international · 2025Article
- The Role of the Dysregulation of circRNAs Expression in Glioblastoma Multiforme.Journal of molecular neuroscience : MN · 2025Review
- Sialylation-related gene signature predict prognosis and immunotherapy efficacy in low- and high-grade glioma: a PCA-based stratification study.Frontiers in oncology · 2025Article
- Sialylation-immune-related lncRNAFrontiers in immunology · 2025Article
- Exploring the common mechanisms and biomarker ST8SIA4 of atherosclerosis and ankylosing spondylitis through bioinformatics analysis and machine learning.Frontiers in cardiovascular medicine · 2024Article
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Authors and funding
25 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expressions. Mechanistically, BRCA1 deficiency increased expression of VEGFA and IL6 to activate TGFβ-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA. SIGNIFICANCE: BRCA1 deficiency generates an acidic microenvironment to promote cancer metastasis and immunotherapy resistance that can be reversed using a sialyltransferase inhibitor.
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