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

作者：Meggy Suarez‐Carmona, Mareike Hampel, Xin-Wen Zhang, Alexandra Pöchmann, Silke 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 E. Baracos, Mathias Heikenwalder, Laurence Zitvogel, Xinyi Xu, Chenqi Xu, Michael Volkmar, Daniel Schraivogel, Lars M. Steinmetz, Junzo Hamanishi, Masaki Mandai, Matthias M. Gaida, Theresa Mokry, Johanna Nattenmüller, Oliver Sedlaczek, Nanna Monje, Roxana Schwab, Annette Hasenburg, Athanasios Mavratzas, Regina Boger, Frederik Marmé, Sarah Schott, Niels Halama · 发表于：Signal Transduction and Targeted Therapy · 年份：2026 · DOI：10.1038/s41392-026-02594-8 · 被引用次数：2 · 研究领域：Immune cells in cancer、Ovarian cancer diagnosis and treatment、Ferroptosis and cancer prognosis

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 immu...