Tumor sialylation controls effective anti-cancer immunity in breast cancer

ABSTRACT: Breast cancer is the most prevalent cancer among women, yet immune checkpoint inhibitors remain largely ineffective in the majority of patients. To better understand the mechanisms underlying immune evasion in breast cancer, we analyzed two independent clinical cohorts and identified a negative association between tumor sialylation and T cell infiltration across molecular subtypes, most prominently in luminal B tumors. In preclinical models, both genetic and pharmacologic inhibition of tumor cell sialylation reshape the tumor microenvironment by reducing neutrophil and PMN-MDSC infiltration, while CD8⁺ effector and Tcf7⁺ memory T cells are increased within the mammary tumors. Mechanistically, sialylation enhances the serum half-life of granulocyte colony-stimulating factor (G-CSF), a key driver of neutrophilic immunosuppression, and dampens tumor cell immunogenicity by limiting MHC-I surface expression. Disruption of sialylation sensitizes resistant mammary tumors to CD8⁺ T cell-mediated killing and synergizes with anti-PD-1 therapy in multiple breast cancer models. Analysis of patient datasets further reveals a sialylation gene signature enriched in breast tumors, especially of the luminal B subtype, that correlates with increased neutrophils and poor CD8⁺ T cell infiltration. Our findings establish tumor cell sialylation as a central regulator of immune evasion in breast cancer, offering a therapeutic vulnerability to unlock anti-tumor immunity and improve responsiveness to immune checkpoint inhibitors.

ORGANISM(S): Mus musculus

PROVIDER: GSE307142 | GEO | 2026/04/25

REPOSITORIES: GEO