Spatial Profiling Reveals Unique Immune Microenvironment in Premenopausal Triple-Negative Breast Cancer Associated with Therapy Response

Triple-negative breast cancer (TNBC) lacks targeted therapies, leading to poor prognosis. Younger TNBC patients exhibit distinct tumor microenvironments and aggressive disease. We explored the influence of menopausal status on immune landscapes, tumor progression, and therapy response using spatial profiling. Eleven treatment-naïve TNBC tumors were analyzed in epithelial and non-epithelial areas, revealing distinct clusters for premenopausal tumors with upregulated antigen presentation and cell activation pathways, and downregulated T cell checkpoint and PI3K-AKT pathways. External dataset validation (METABRIC, SCAN-B) associated these findings with better prognosis in premenopausal tumors. Immune profiling showed increased CD8 + T cells, monocytes, and endothelial cells, with higher intratumoral CD8, CD4, and CD20 protein expression. Therapy response analysis (I-SPY 2) indicated better responses to PARP and HSP90 inhibitors but reduced sensitivity to pembrolizumab and PI3K-AKT inhibitors in premenopausal tumors. These results highlight menopausal status as a critical factor in TNBC therapy and underscore the need for tailored treatment strategies.