Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer
Summary
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 b
Content
# Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer
*Published: 2026 Mar 4*
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.
DOI: 10.1038/s41392-026-02594-8