Cancer-Associated Fibroblast Exosomes in Breast Cancer: Mechanisms of Tumor-Stroma Crosstalk and Clinical Implications.

Abstract

Breast cancer progression is shaped by a continuous exchange of signals between tumor cells and the surrounding stroma, in which cancer-associated fibroblasts (CAFs) are among the most influential partners. This review concentrates on CAF-derived exosomes as the principal vehicles of that exchange, and on how their cargo and mode of delivery differ across functionally distinct CAF subtypes. Exosomes are nanoscale vesicles that carry microRNAs (miRNAs), long noncoding RNAs, proteins, and metabolites between cells, and CAF-derived vesicles have been linked to epithelial-mesenchymal transition (EMT), angiogenesis, metabolic rewiring, and resistance to chemotherapy, radiotherapy, and endocrine therapy. In estrogen receptor-positive disease, exosomal miR-22 delivered by CD63⁺ CAFs silences ESR1 and PTEN and blunts the response to tamoxifen, while proteins such as ADAM10 and the long noncoding RNA SNHG3 have been tied to motility and glycolytic reprogramming. The immune consequences are equally important, although the evidence here is thinner than is often implied: vesicular PD-L1 suppresses T cell priming, and spatially resolved studies now place distinct FAP⁺ CAF states next to specific macrophage and regulatory lymphocyte populations. Not all CAFs behave this way. Meflin⁺ and CD146⁺ subsets restrain tumor growth, which is why indiscriminate stromal depletion has repeatedly failed and why subtype-selective approaches are needed. We also consider the practical obstacles that still limit translation, including vesicle heterogeneity, the difficulty of separating exosomes from other small extracellular vesicles, and the absence of validated biomarkers.