Objectives <p>The YAP/TAZ pathway is implicated in both obesity and breast cancer (BRCA), but the specific effector genes common to both diseases are unknown. We aimed to identify these shared YAP/TAZ effectors.</p> Methods <p>We integrated transcriptomic data from BRCA (TCGA, GSE42568) and obesity (GSE25401, GSE151839) datasets. YAP/TAZ-related genes were identified through differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms. The tumor immune microenvironment was profiled using xCell, ESTIMATE, IPS and TIDE algorithms. The prognostic value was assessed in an independent cohort (GSE25065). Experimental validation was performed using clinical specimens via RT-qPCR.</p> Results <p>F2R and MXRA5 were identified as core YAP/TAZ-effector genes associated with obesity and BRCA. F2R was upregulated in obese adipose tissue, and both genes exhibited transcriptional dysregulation in BRCA cohorts, though not all differences reached statistical significance between tumor and adjacent normal tissues. Comprehensive immune profiling showed that high expression of F2R/MXRA5 was associated with an immunosuppressive microenvironment, exhibiting reduced infiltration of dendritic cells and macrophages, elevated TIDE scores, and decreased tumor purity. Critically, high expression of either gene predicted significantly poorer overall survival in patients with triple-negative breast cancer (TNBC). Furthermore, computational analysis revealed a positive correlation between F2R/MXRA5 expression and predicted resistance to the HDAC inhibitor Vorinostat, suggesting a potential association with epigenetic therapy resistance.</p> Conclusion <p>F2R and MXRA5 are novel biomarkers linking obesity to BRCA immunosuppression and poor outcomes, offering potential for risk stratification and combination therapy.</p>