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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月4日

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

摘要

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.