Multi‑scale immune and spatial profiling of sclerosing adenosis and surrounding breast tissue identifies an immune‑cold field phenotype associated with breast cancer risk

作者：Nicole Cruz-Reyes, Hongling Liang, Melody Stallings-Mann, Laura Pacheco-Spann, Bryan M. McCauley, Yuanhang Liu, Robert A. Vierkant, Jessica Fischer, Denice Gehling, Lisa R. Seymour, AC Degnim, Mark E Sherman, Stacey J. Winham, Derek C. Radisky · 发表于：Breast Cancer Research · 年份：2026 · DOI：10.1186/s13058-026-02293-w · 研究领域：Breast Lesions and Carcinomas、Biomarkers in Disease Mechanisms、Systemic Sclerosis and Related Diseases

BACKGROUND: Benign breast disease (BBD) is common and confers heterogeneous increases in breast cancer risk; however, risk prediction relies mainly on histopathology and clinical factors. Sclerosing adenosis (SA) is a proliferative BBD lesion associated with an approximately two-fold increase in risk, yet most women with SA never develop breast cancer. We hypothesize that the immune-stromal microenvironment of SA and its surrounding lobular field relates to subsequent invasive breast cancer. METHODS: In a nested case-control study within a BBD cohort, we profiled 24 sclerosing adenosis (SA) biopsies (9 developing invasive breast cancer within 15 years, cases; 15 cancer-free at ≥ 15 years, controls). We integrated whole-tissue NanoString gene-expression profiling with multiplex immunofluorescence (MxIF) imaging of SA lesions and surrounding morphologically normal lobules. We measured immune and stromal biomarkers in SA lesions and adjacent lobules, with image analysis masked to case-control status, integrated these data with whole-tissue gene expression, and summarized both microenvironment patterns and the proximity of immune cells to proliferating epithelium. RESULTS: SA biopsies from women who later developed cancer showed a low-immune, high-stromal gene-expression program, whereas controls were enriched for immune signatures. Stromal densities of CD8⁺, CD68⁺ and RUNX3⁺ cells in both lobular stroma and SA lesions mirrored this axis and were markedly lower in cases than cont...