Macrophage-associated epithelial–mesenchymal transition in human breast cancer: contextualizing innate immune sensing programs

To determine whether innate immune-sensing activity is associated with epithelial–mesenchymal transition (EMT) and related tumor-aggressiveness programs in human breast cancer. We analyzed RNA sequencing and clinical data from The Cancer Genome Atlas breast cancer cohort ( n = 1087). Gene expression-based signatures were constructed for innate immune sensing, interferon signaling, CD8 T cells, macrophages, EMT, invasion, and metastasis. Associations were evaluated using Pearson correlation, Cox proportional hazards models, and multivariable linear regression, including adjustment for PAM50 molecular subtype and immune cell signatures. Innate immune-sensing signatures were strongly correlated with interferon signaling ( r = 0.73) and macrophage-associated signatures ( r = 0.77), indicating a coordinated inflammatory program. Innate immune sensing was moderately associated with EMT ( r = 0.48), invasion ( r = 0.45), and metastasis-related transcriptional programs ( r = 0.48). In multivariable models, innate immune sensing remained associated with EMT after adjustment for molecular subtype and immune cell signatures ( β = 0.17, P < 0.001), while macrophage signatures were the dominant predictors ( β = 0.51, P < 2 × 10 −16 ) and CD8 signatures were inversely associated ( β = −0.14, P < 0.001). No association with overall survival was observed. Innate immune-sensing signatures are associated with macrophage-driven EMT programs in breast cancer, consistent with activation of inflammatory pathways within the tumor microenvironment.