Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction PMID: 40595293

ADC Targets in Oncology

2026-04-10

Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

Commun Biol. 2025 Jul 1;8(1):976. doi: 10.1038/s42003-025-08339-7.

Kathrin Fuchs ¹ , Elisabetta D'Avanzo ¹ , Isabell Armstark ¹ , Ruthger van Roey ¹ , Ana Clavel Ezquerra ¹ , Nino Bindel ¹ , Katharina Siebenkäs ¹ , Yussuf Hajjaj ¹ , Renato Liguori ² ³ , Fulvia Ferrazzi ² ³ , Lukas Amon ⁴ , Johanna Bulang ⁵ , Julian Hübner ⁵ , Marcel Edler ⁵ , Ece Grace ¹ , Annemarie Schwab ¹ , Marwin Alfredo ¹ , Maria Faas ⁶ , Jochen Ackermann ⁶ , Elena Percivalle ⁷ , Claudia Günther ⁷ ⁸ , Markus H Hoffmann ⁹ , Gerhard Krönke ⁶ ⁸ ¹⁰ , Christoph Becker ⁸ ¹¹ , Diana Dudziak ⁴ ⁸ ¹² ¹³ ¹⁴ ¹⁵ ¹⁶ , Philipp Arnold ¹⁷ , Miriam Woehner ⁵ , Falk Nimmerjahn ⁵ ¹² ¹⁵ , Simone Brabletz ¹ , Marc P Stemmler ¹ , Thomas Brabletz ^# ¹ ¹⁴ , Harald Schuhwerk ^# ¹⁸ ¹⁹

Affiliations

1. Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
2. Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
3. Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
4. Department of Dermatology, Laboratory of Dendritic Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
5. Division of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
6. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
7. Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
8. Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
9. Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
10. Department of Rheumatology and Clinical Immunology, Charite Universitätsmedizin Berlin, Berlin, Germany.
11. Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
12. Medical Immunology Campus Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
13. Institute of Immunology, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
14. Comprehensive Cancer Center Erlangen - European Metropolitan Area of Nuremberg (CCC-EMN), Erlangen, Germany.
15. FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
16. Comprehensive Cancer Center Central Germany (CCCG) Jena, Jena, Germany.
17. Institute of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
18. Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. [email protected].
19. Universitätsklinikum Erlangen, Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Erlangen, Germany. [email protected].
# Contributed equally.

Abstract

Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic Cancer with cell type-specific deletion of the epithelial-to-mesenchymal transition driver Zeb1, which is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking and anti-tumor immune responses. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CXCL10, CCL2 and CCL22, by regulating their biosynthesis, vesicular transport and release. This elevates cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for therapeutic CD8 + T cell addition. Our study identifies ZEB1 in TAMs as a facilitator of anti-tumor immunity, suggests a window of opportunity for cytokine-guided CTL tropism and reinforces the importance of onco-immunological context, particularly in the design of macrophage- and/or cytokine-depleting strategies.