Tumor sialylation regulates G-CSF stability and promotes neutrophil-mediated immunosuppression in breast cancer.

Breast cancer is the most prevalent cancer among women, yet immune checkpoint inhibitors remain largely ineffective in the majority of patients. Here we show that tumor sialylation is negatively associated with T cell infiltration across molecular breast cancer subtypes. In preclinical models, both genetic and pharmacologic inhibition of tumor cell sialylation reshape the tumor microenvironment by reducing immunosuppressive neutrophil 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 anti-PD-1 therapy in multiple breast cancer models. These findings establish tumor sialylation as a key mechanism of immune evasion and a potential therapeutic target in breast cancer.