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

Abstract 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, ER α 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.