Predicting immune responsiveness in ER-positive breast cancer for personalized therapy: a population-based study

The immune system's role in estrogen receptor (ER)-positive breast cancer is poorly understood. A population-based cohort of 428 breast cancer patients with clinical and molecular data was analyzed to assess how immune biomarkers can inform treatment decisions. Tumor-intrinsic immune responsiveness and local immune infiltration were quantified, and epithelial cell states were derived using EcoTyper. The interaction between ProliferativeIndex and Immunescore predicted risk of local recurrence in ER-positive tumors (HR 0.56, 95% CI 0.36-0.88, p = 0.012). EcoTyper identified two epithelial cell states, S04 and S05, with distinct immunomodulatory properties. S04 tumors showed higher proliferation, enrichment for M1 macrophages, CD8 effector T-cells, and plasma cells, alongside hypomethylation of immune-related pathways and hypermethylation of the PI3K signaling pathway. In contrast, S05-enriched tumors were associated with fibroblast activation, immune exclusion, and enrichment for glycosylation-related pathways. These findings suggest that epithelial cell states shape immune responsiveness in ER-positive breast cancer and may inform biomarker-driven treatment strategies.