Abstract
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.
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Acknowledgements
We thank all members of our laboratories for their support and help. We thank all in-house core facilities, especially BioOptics Facility, Proteomics Facility, Molecular Biology Service, as well as the VBCF Histology facility and Next Generation Sequencing facility.
Funding
S.M. received funding from the European Union’s Horizon 2020 research and innovation Programme under the Marie Sklodowska-Curie grant agreement No 841319 and Austrian Science Fund (FWF, Project numbers: ESP 166 and PIN 9259824). G.J. was supported by a DOC fellowship from the Austrian Academy of Sciences. O.H.A. received funding from the Swiss National Science Foundation (SNSF, grant No P400PM_194473) and the Bruno Bloch Foundation. Work in J.M.P.‘s laboratory is supported by the Austrian Federal Ministry of Education, Science and Research, the Austrian Academy of Sciences, the City of Vienna and grants from the European Research Council (ERC Advanced grant 341036), the Austrian Science Fund (FWF Wittgenstein award Z 271-B19), the T. von Zastrow foundation, and a Canada 150 Research Chairs Program (F18-01336).
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Mereiter, S., Jonsson, G., Oliveira, T. et al. Tumor sialylation regulates G-CSF stability and promotes neutrophil-mediated immunosuppression in breast cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73401-9
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DOI: https://doi.org/10.1038/s41467-026-73401-9
