Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma PMID: 39890772

ADC Targets in Oncology

2026-04-10

Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma

Nat Commun. 2025 Jan 31;16(1):1217. doi: 10.1038/s41467-025-55969-w.

Mengzhu Sun ¹ , Laure Garnier ¹ , Romane Chevalier ¹ , Martin Roumain ² , Chen Wang ¹ ³ , Julien Angelillo ¹ , Julien Montorfani ¹ , Robert Pick ¹ , Dale Brighouse ¹ , Nadine Fournier ⁴ , David Tarussio ⁵ ⁶ ⁷ , Stéphanie Tissot ⁵ ⁶ ⁷ , Jean-Marc Lobaccaro ⁸ ⁹ ¹⁰ , Tatiana V Petrova ⁷ ¹¹ , Camilla Jandus ¹ ⁷ ¹² ¹³ , Daniel E Speiser ¹¹ , Manfred Kopf ¹⁴ , Caroline Pot ¹⁵ , Christoph Scheiermann ¹ ¹² ¹³ ¹⁶ , Krisztian Homicsko ¹¹ , Giulio G Muccioli ² , Abhishek D Garg ¹⁷ , Stéphanie Hugues ¹⁸ ¹⁹ ²⁰

Affiliations

1. Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland.
2. Metabolism and Nutrition Research Group, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
3. National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China.
4. Translational Data Science (TDS), Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
5. Swiss Cancer Center Leman, Lausanne, Switzerland.
6. Department of Oncology, Center for Experimental Therapeutics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
7. Ludwig Institute for Cancer Research, Lausanne, Switzerland.
8. Université Clermont Auvergne, iGReD, CNRS UMR 6293, INSERM U1103, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France.
9. Groupe Cancer Clermont Auvergne, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France.
10. Centre de Recherche en Nutrition Humaine d'Auvergne, 58 Boulevard Montalembert, F-63009, Clermont-Ferrand, France.
11. Department of Oncology, University of Lausanne, Lausanne, Switzerland.
12. Geneva Centre for Inflammation Research, Geneva, Switzerland.
13. Translational Research Centre in Oncohaematology, Geneva, Switzerland.
14. Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
15. Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
16. Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter-Brendel-Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany.
17. Laboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine (CMM), KU Leuven, Belgium.
18. Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. [email protected].
19. Geneva Centre for Inflammation Research, Geneva, Switzerland. [email protected].
20. Translational Research Centre in Oncohaematology, Geneva, Switzerland. [email protected].

Abstract

In melanoma, lymphangiogenesis correlates with metastasis and poor prognosis and promotes immunosuppression. However, it also potentiates immunotherapy by supporting immune cell trafficking. We show in a lymphangiogenic murine melanoma that lymphatic endothelial cells (LECs) upregulate the enzyme Ch25h, which catalyzes the formation of 25-hydroxycholesterol (25-HC) from Cholesterol and plays important roles in lipid metabolism, gene regulation, and immune activation. We identify a role for LECs as a source of extracellular 25-HC in tumors inhibiting PPAR-γ in intra-tumoral macrophages and monocytes, preventing their immunosuppressive function and instead promoting their conversion into proinflammatory myeloid cells that support effector T cell functions. In human melanoma, LECs also upregulate Ch25h, and its expression correlates with the lymphatic vessel signature, infiltration of pro-inflammatory macrophages, better patient survival, and better response to immunotherapy. We identify here in mechanistic detail an important LEC function that supports anti-tumor immunity, which can be therapeutically exploited in combination with immunotherapy.