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.