Targeting Monocyte Dysregulation in Ovarian Cancer: Insights from Single-Cell Genomics and Mendelian Randomization

Background Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies, primarily due to delayed diagnosis and a profoundly immunosuppressive tumor immune microenvironment (TIME) that fosters immune evasion and therapeutic resistance. Among immune cell types, monocytes are emerging as key regulators within the TIME, influencing tumor progression through diverse immunological mechanisms. However, their direct causal roles in OC pathogenesis remain largely unexplored. Method To investigate the causal involvement of monocytes in OC, we integrated single-cell RNA sequencing datasets from the GEO and TISCH databases. Rigorous quality control and dimensionality reduction were performed using Seurat and SingleR, identifying eight major cell types, including an enrichment of monocytes in OC samples. Cell–cell communication networks were mapped with CellChat to characterize interactions between monocytes and other cell types via immunomodulatory ligand–receptor pairs, such as macrophage migration inhibitory factor (MIF) and midkine (MDK). Causal gene identification was carried out using Mendelian randomization and Bayesian colocalization analyses across multiple genome-wide association study (GWAS) datasets, including FinnGen. Result We identified five monocyte-related genes—SGK1, PRKCA, TBC1D4, VPS8, and PPFIBP2—that demonstrated consistent causal associations with OC risk. Functional enrichment analyses revealed that these genes are involved in key oncogenic pathways, including PI3K-Akt and MAPK signaling. In vitro experiments further validated that SGK1 is upregulated in M2-like macrophages and contributes to tumor cell invasion. Pharmacologic inhibition of SGK1 using Si113 reversed immunosuppressive phenotypes, supporting its role as a potential therapeutic target. Collectively, these findings highlight monocyte-associated genes—particularly SGK1—as promising targets for immunotherapy in ovarian cancer. Conclusion This study integrates single-cell transcriptomics and Mendelian randomization to identify five monocyte-related genes causally linked to ovarian cancer (OC) risk. Among them, SGK1 may play a key role in promoting immunosuppressive macrophage polarization and tumor progression, highlighting its potential as a therapeutic target to remodel the OC immune microenvironment.Keywords: Ovarian cancer; Monocytes; Tumor immune microenvironment; Mendelian randomization; Bayesian colocalization; Single-cell RNA sequencing