Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer

Immunotherapy with immune checkpoint blockade (ICB) in epithelial ovarian carcinoma (EOC) shows limited clinical benefit only for a small subset of patients. Overall response rates are low, so that overcoming immunotherapy resistance and improved stratification are key. In this study, we investigated the immunometabolic landscape of EOC with a focus on omental metastases, identifying lipid-laden macrophages as central elements for actionable therapeutic vulnerabilities and giving rise to biomarkers for improved patient stratification. Using patient-derived explants, we demonstrated a functional dichotomy inside the typically lipid-rich microenvironment of omental metastases: augmented maintenance of effector T cell function, while lipid uptake and processing by tumor-associated macrophages (TAMs) induces oxidative stress-dependent signaling programs, which drive macrophage dysfunction and immune suppression. Pharmacological modulation of lipid-driven signaling pathways through CCR5 inhibition (inflammation modulation through maraviroc) or blockade of the lipid scavenger receptor CD36 reprograms TAMs, restores T cell activity, and enhances antitumor immune responses within lipid-rich tumor niches. Mechanistically, studies in humanized mouse models reveal that maraviroc-mediated CCR5 inhibition induces transcriptional programs associated with immune activation in stressed, lipid-laden human TAMs. Consistent with these mechanistic insights, we demonstrated that the specific immunometabolic niche in omental metastases is clinically associated with responsiveness to ICB. We propose a non-invasive radiomics and machine-learning-based analysis of imaging data to assess omental involvement for patient stratification.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2026-03-04
DOI
https://doi.org/10.1038/s41392-026-02594-8
Primary Topic
Immune cells in cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer

Pornpimol Charoentong, Oliver Sedlaczek, Lars Michael Steinmetz, Jannis Wißfeld et al.
Signal Transduction and Targeted Therapy
Immune cells in cancer
article

Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer

Pornpimol Charoentong, Oliver Sedlaczek, Lars Michael Steinmetz, Jannis Wißfeld, Nektarios A. Valous, Vickie E. Baracos, Theresa Mokry, Sarah Schott, Mareike Hampel, Daniel Schraivogel, Matthias M. Gaida, Michael Volkmar, Stanislas Goriely, Roxana Schwab, Meggy Suarez‐Carmona, Aurélie Detavernier, Athanasios Mavratzas, Silke Grauling-Halama, Abdulkader Azouz, Alexandra Pöchmann, Jürgen G. Okun, Regina Boger, Sven Zukunft, Dyke Ferber, Junzo Hamanishi, Chenqi Xu, Mathias Heikenwalder, Masaki Mandai, Johanna Nattenmüller, Niels Halama, Annette Hasenburg, Frederik Marmé, Nanna Monje, Xin-Wen Zhang, Anthony Rongvaux, Laurence Zitvogel, Ingrid Fleming, Alicia Höflich, Xinyi Xu
article en

Abstract

Immunotherapy with immune checkpoint blockade (ICB) in epithelial ovarian carcinoma (EOC) shows limited clinical benefit only for a small subset of patients. Overall response rates are low, so that overcoming immunotherapy resistance and improved stratification are key. In this study, we investigated the immunometabolic landscape of EOC with a focus on omental metastases, identifying lipid-laden macrophages as central elements for actionable therapeutic vulnerabilities and giving rise to biomarkers for improved patient stratification. Using patient-derived explants, we demonstrated a functional dichotomy inside the typically lipid-rich microenvironment of omental metastases: augmented maintenance of effector T cell function, while lipid uptake and processing by tumor-associated macrophages (TAMs) induces oxidative stress-dependent signaling programs, which drive macrophage dysfunction and immune suppression. Pharmacological modulation of lipid-driven signaling pathways through CCR5 inhibition (inflammation modulation through maraviroc) or blockade of the lipid scavenger receptor CD36 reprograms TAMs, restores T cell activity, and enhances antitumor immune responses within lipid-rich tumor niches. Mechanistically, studies in humanized mouse models reveal that maraviroc-mediated CCR5 inhibition induces transcriptional programs associated with immune activation in stressed, lipid-laden human TAMs. Consistent with these mechanistic insights, we demonstrated that the specific immunometabolic niche in omental metastases is clinically associated with responsiveness to ICB. We propose a non-invasive radiomics and machine-learning-based analysis of imaging data to assess omental involvement for patient stratification.

Signal Transduction and Targeted TherapyVol. 11(1)
Goethe University Frankfurt (DE), University of Alberta (CA), University of Freiburg (DE), University of Mannheim (DE), German Cancer Research Center (DE), Johannes Gutenberg University Mainz (DE), Medical University of Graz (AT), Kyoto University (JP), Heidelberg University (DE), Institut Gustave Roussy (FR), University Hospital Heidelberg (DE), Fred Hutch Cancer Center (US), University Medical Center of the Johannes Gutenberg University Mainz (DE), National Center for Tumor Diseases (DE), Helmholtz Institute Mainz (DE), Hopp Children's Cancer Center Heidelberg (DE), Center for Excellence in Molecular Cell Science (CN), German Centre for Cardiovascular Research (DE), Institute of Immunology (HR), European Molecular Biology Laboratory (DE), Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz (DE), DKFZ-ZMBH Alliance (DE), University Medical Centre Mannheim (DE), University of Chinese Academy of Sciences (CN), Stanford University (US)
Yale University, Deutsches Krebsforschungszentrum, Regeneron Pharmaceuticals, European Molecular Biology Laboratory, Deutsche Forschungsgemeinschaft, Fonds De La Recherche Scientifique - FNRS, European Regional Development Fund
Openalex Percentile: Top 35%
Immune cells in cancer
DOIOpen Access PDFOpenAlex
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