A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer PMID: 40957419

Target-related Cytokines

2026-09-23

A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer

Immunity. 2025 Sep 15:S1074-7613(25)00378-4. doi: 10.1016/j.immuni.2025.08.015.

Greta Mattavelli ¹ , Moutaz Helal ¹ , Ana Cetkovic ¹ , Maximilian J Krämer ¹ , Saskia-Laureen Herbert ² , Kilian Mielert ³ , Tanja Schlaiß ² , Anna Frank ¹ , Emily Riemer ¹ , Mara John ¹ , Josefina Del Pilar Martinez Vasquez ¹ , Laura Kindl ¹ , Jonathan J Swietlik ⁴ , Benedikt O Gansen ⁵ , Marion Krafft ¹ , Emilia Stanojkovska ¹ , Hanna Fischer ¹ , Ute-Susann Albert ² , Jonas Bauer ² , Murilo Delgobo ⁶ , Arpa Aintablian ⁷ , Haisam Alattar ⁸ , Manfred B Lutz ⁷ , Felix Meissner ⁹ , Thordur Oskarsson ¹⁰ , Leo Rasche ¹¹ , Gustavo Ramos ⁶ , Andreas Rosenwald ³ , Achim Wöckel ² , Angela Riedel ¹²

Affiliations

1. Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg and University Würzburg, Würzburg, Germany.
2. Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany.
3. Institute of Pathology, University of Würzburg, Würzburg, Germany.
4. Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.
5. Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany.
6. Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
7. Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
8. Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany; Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
9. Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany; Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany.
10. Department of Molecular Oncology and Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
11. Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg and University Würzburg, Würzburg, Germany; Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
12. Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg and University Würzburg, Würzburg, Germany; Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany. Electronic address: [email protected].

Abstract

Tumor-draining Lymph Nodes (TDLNs) are sites of anti-tumor immune priming as well as metastases. Here, we examined how the cellular networks within TDLNs are reorganized in Triple-Negative Breast Cancer (TNBC). We found that the frequencies of programmed death ligand 1 high (PD-L1^hi) monocytes increased in TDLNs of metastatic TNBC mouse Tumors. Fibroblastic reticular cell (FRC) subtypes heightened the expression of the chemokines CCL2 and CCL7, supporting the homing of CCR2⁺ monocytes. These monocytes suppressed T cells in vitro via PD-L1 and inducible nitric oxide synthase (iNOS). Spatial transcriptomics revealed immunosuppressive FRC-monocyte niches in vascularized and T cell areas. Tumor-associated Toll-like Receptor (TLR) 4 ligands induced CCL2 and CCL7 expression by FRCs to promote monocyte recruitment. Localized TLR4 inhibition in combination with anti-programmed cell death protein 1 (αPD-1) therapy reduced monocyte homing and boosted T cell function, ultimately attenuating lung metastases. Monocytes accumulate in human TNBC TDLNs, with evidence of a FRC-monocyte axis, and a TLR4 Ligand signature is predictive of poor survival outcomes in TNBC patients. Thus, metastatic TNBC can reprogram Lymph Nodes (LNs) to facilitate PD-L1-mediated immune evasion and metastasis.

Keywords

fibroblastic reticular cells; immunosuppressive monocytes; immunotherapy; metastasis; pre-metastatic niche; single-cell sequencing; spatial transcriptomics; triple-negative breast cancer; tumor microenvironment; tumor-draining lymph node.