Obesity- and tumor-derived signals drive cancer-associated state transitions in breast mesenchymal stromal/stem cells reprogrammed by IL1RA or JAK inhibition

Abstract The tumor microenvironment (TME) in breast cancer is shaped by reciprocal interactions between cancer cells and their surrounding stromal populations. Here, we show that breast adipose tissue-derived stromal/stem cells (bASCs) undergo distinct state transitions in response to tumor cues and systemic metabolic status. Using primary bASCs derived from tumor-adjacent and tumor-distant adipose tissues of breast cancer patients with or without obesity, we identify two functionally distinct, tumor-educated stromal phenotypes: a cytokine-rich inflammatory CAF-like (iCAF) state predominating in lean-adjacent bASCs (ln-aT), and a myofibroblastic CAF-like (myCAF) state emerging in obese-adjacent bASCs (ob-aT). Importantly, transforming growth factor β (TGFβ) is sufficient to induce myCAF-like reprogramming in obesity-primed bASCs, while interleukin 1 (IL1)-Janus kinase (JAK) signaling promotes iCAF features. Re-analysis of single-cell RNA-seq data of breast cancer samples reveals an increased TGFβ expression across stromal and immune cell types in individuals with obesity. Mechanistically, IL1 receptor blockade (anakinra) or JAK inhibition (AZD1480) reverses both iCAF and myCAF phenotypes and functionally suppresses stromal-driven epithelial-mesenchymal transition as well as cancer stemness in breast cancer cells. These findings establish a mechanistic link between obese cues, stromal plasticity, and breast cancer progression, and reveal IL1/JAK signaling as a tractable axis to therapeutically reprogram the breast cancer stroma. Graphical Abstract