Targeting monocyte dysregulation in ovarian cancer: insights from single-cell genomics and Mendelian randomization

Ovarian cancer (OC) lethality is frequently associated with an immunosuppressive tumor immune microenvironment (TIME). While monocytes appear to function as notable regulators within the TIME, their causal involvement in OC pathogenesis remains poorly defined.

To investigate the causal involvement of monocytes in OC, we integrated single-cell RNA sequencing datasets from the GEO and TISCH databases. Comparative cell proportion analysis was conducted using Fisher's exact test. Cell-cell communication networks were mapped with CellChat to characterize tumor-specific interactions via ligand-receptor pairs (e.g., MIF, MDK). Causal associations were identified through Summary-data-based Mendelian randomization (MR) and two-sample MR, integrating eQTLGen statistics (n = 31,684) with OC GWAS data (1,588 cases). Instrumental variables were prioritized based on F-statistics > 10 and LD clumping. Bayesian colocalization and the HEIDI test (P > 0.05) were employed to rule out linkage disequilibrium. Finally, functional roles of candidate genes were validated via qRT-PCR, Western blot, and in vitro polarization assays.

Quantitative analysis revealed a significant enrichment of monocytes in the OC group (24.58%) compared to healthy controls (2.44%, P < 0.001), which was independently validated by immunofluorescence staining. CellChat identified tumor-specific signaling axes, including MIF-(CD74 + CXCR4) and MDK-NCL, that were predominantly active in the OC microenvironment but nearly quiescent in healthy tissues. We identified five monocyte-related genes-SGK1, PRKCA, TBC1D4, VPS8, and PPFIBP2-that demonstrated consistent causal associations with OC risk and passed the HEIDI test (P > 0.05), ruling out linkage disequilibrium. Functional enrichment suggested these genes modulate PI3K-Akt and MAPK signaling. In vitro assays confirmed that SGK1 is specifically upregulated in M2-polarized macrophages. Furthermore, pharmacological inhibition of SGK1 using si113 significantly reversed the immunosuppressive M2 phenotype and impaired tumor cell invasion, highlighting its potential as a precision therapeutic target.

This study integrates single-cell transcriptomics and MR to identify five monocyte-related genes causally linked to OC risk. Among them, SGK1 may play a substantial role in promoting immunosuppressive macrophage polarization and may represent a promising therapeutic target to remodel the TIME and enhance anti-tumor immunity in OC.