CD63+ Cancer-Associated Fibroblasts Confer Tamoxifen Resistance to Breast Cancer Cells through Exosomal miR-22

Tamoxifen remains the most effective treatment for Estrogen Receptor α (ERα)-positive breast Cancer. However, many patients still develop resistance to tamoxifen in association with metastatic recurrence, which presents a tremendous clinical challenge. To better understand tamoxifen resistance from the perspective of the tumor microenvironment, the whole microenvironment landscape is charted by single-cell RNA sequencing and a new cancer-associated fibroblast (CAF) subset, CD63⁺ CAFs, is identified that promotes tamoxifen resistance in breast Cancer. Furthermore, it is discovered that CD63⁺ CAFs secrete exosomes rich in miR-22, which can bind its targets, ERα and PTEN, to confer tamoxifen resistance on breast Cancer cells. Additionally, it is found that the packaging of miR-22 into CD63⁺ CAF-derived exosomes is mediated by SFRS1. Furthermore, CD63 induces STAT3 activation to maintain the phenotype and function of CD63⁺ CAFs. Most importantly, the pharmacological blockade of CD63⁺ CAFs with a CD63-neutralizing antibody or cRGD-miR-22-sponge nanoparticles enhances the therapeutic effect of tamoxifen in breast Cancer. In summary, the study reveals a novel subset of CD63⁺ CAFs that induces tamoxifen resistance in breast Cancer via exosomal miR-22, suggesting that CD63⁺ CAFs may be a novel therapeutic target to enhance tamoxifen sensitivity.