Metabolic reprogramming of tumor-associated macrophage clusters in ovarian cancer: a single-cell transcriptomic analysis and prognostic model.

PURPOSE: The complex tumor microenvironment (TME) in ovarian cancer (OC), particularly the role of macrophage clusters, plays a pivotal role in driving cancer progression and determining patient prognosis. Metabolic reprogramming is a hallmark of tumorigenesis and is crucial in reshaping the TME and driving tumor progression. METHODS: Through a comprehensive single-cell RNA sequencing analysis of macrophage clusters in OC, this study integrated data from four independent datasets and identified hypermetabolic subpopulations within nine distinct mononuclear phagocyte clusters. RESULTS: The identified clusters were notably enriched in pathways related to the TCA cycle, glycolysis, and HIF-1 signaling, which are closely linked to tumor invasiveness and immune modulation. Transcriptional regulation analysis revealed key drivers of these metabolic changes, including ZNF574, BRCA1, and ATF5, which might be potential therapeutic targets. Cell-cell communication analysis demonstrated that hypermetabolic macrophage clusters engaged in extensive signaling with tumor epithelial cells, thereby influencing the immune TME and potentially contributing to immune evasion. A metabolism-related prognostic model was also established based on differentially expressed genes within hypermetabolic macrophages, which exhibited robust predictive power for overall survival in OC patients. CONCLUSIONS: Our findings reveal strong associations between metabolic reprogramming in tumor-associated macrophages and OC progression, suggesting their potential importance in shaping the TME. This study provides novel insights into possible therapeutic strategies and prognostic tools for OC, which warrant further functional validation. CLINICAL TRIAL NUMBER: Not applicable.