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. Tumor sialylation has been associated with different mechanisms of immune evasion. Here the authors show that tumor sialylation regulates G-CSF stability to promote neutrophil-mediated immunosuppression as well dampens tumor cell immunogenicity by limiting MHC-I surface expression, limiting anti-tumor immunity in breast cancer.
Authors
- Gustav Jonsson (ORCID: https://orcid.org/0000-0001-6692-8395)
- Johannes Helm (ORCID: https://orcid.org/0000-0002-6362-0093)
- Magali Lacroix‐Triki (ORCID: https://orcid.org/0000-0002-6641-8536)
- Ann-Kristin Jochum (ORCID: https://orcid.org/0000-0002-6981-1384)
- Wolfram Jochum (ORCID: https://orcid.org/0000-0001-6170-2020)
- Markus Abeln (ORCID: https://orcid.org/0000-0003-4626-7731)
- Marek Feith (ORCID: https://orcid.org/0000-0002-5882-4155)
- Karolina Wasilewska
- Felix Holstein (ORCID: https://orcid.org/0000-0002-3729-9857)
- Stefan Mereiter (ORCID: https://orcid.org/0000-0002-4832-3090)
- Max J. Kellner (ORCID: https://orcid.org/0000-0002-5404-0628)
- Johannes Stadlmann (ORCID: https://orcid.org/0000-0001-5693-6690)
- Vanessa Tkalec
- Lukas Emsenhuber
- Jie Jiao (ORCID: https://orcid.org/0000-0003-2652-8930)
- Ingrid-Judith Garberis
- Josef M. Penninger
- Anja Münster-Kühnel (ORCID: https://orcid.org/0000-0003-0991-7627)
- Anna C. Obenauf (ORCID: https://orcid.org/0000-0002-9556-5914)
- Omar Hasan Ali
- Rita Gerardy-Schahn (ORCID: https://orcid.org/0000-0002-5796-368X)
- Tiago Oliveira (ORCID: https://orcid.org/0000-0003-4759-1728)
- David Hoffmann
- Lukas Flatz
- Guido Kroemer (ORCID: https://orcid.org/0000-0002-9334-4405)
- Laurence Zitvogel (ORCID: https://orcid.org/0000-0003-1596-0998)
Institutions
- Institute of Molecular Biotechnology (AT)
- Austrian Academy of Sciences (AT)
- University of British Columbia (CA)
- Inserm (FR)
- Research Institute of Molecular Pathology (AT)
- University of Zurich (CH)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Kantonsspital St. Gallen (CH)
- Institut Gustave Roussy (FR)
- Medizinische Hochschule Hannover (DE)
- Sorbonne Université (FR)
- Centre de Recherche des Cordeliers (FR)
- La Ligue Contre le Cancer (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- University Hospital of Zurich (CH)
- Hôpital Européen Georges-Pompidou (FR)
- Hôpital Européen (FR)
- Helmholtz Centre for Infection Research (DE)
- University Children's Hospital Tübingen (DE)
- Vienna Biocenter (AT)
- Bicêtre Hospital (FR)
- Medical University of Vienna (AT)
- University of Tübingen (DE)
- BOKU University (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1038/s41467-026-73401-9
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Horizon 2020 Framework Programme