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

## TL;DR

This study explores how lipid-rich environments in ovarian cancer metastases affect immunotherapy and identifies new strategies to improve treatment response.

## Contribution

The study identifies lipid-laden macrophages in omental metastases as actionable targets and proposes new therapeutic and stratification approaches.

## Key findings

- Lipid uptake by tumor-associated macrophages induces immune suppression and oxidative stress.
- CCR5 inhibition or CD36 blockade reprograms macrophages and restores T cell activity in lipid-rich niches.
- A radiomics and machine-learning approach is proposed to assess omental involvement for patient stratification.

## 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.