Rab27b-mediated CAFs derived exosomal miR-22-3p suppresses ferroptosis and promotes cisplatin resistance in osteosarcoma.

Chemoresistance remains a significant hurdle in the cisplatin treatment of osteosarcoma, with poor patient outcomes. Cancer-associated fibroblasts (CAFs) and exosomes play crucial roles in this resistance by transferring miRNAs to cancer cells. In this study, we investigated the biological role of CAFs derived exosomal miR-22-3p in promoting chemoresistance. Using single-cell analysis and tissue exosome miRNAs sequencing, CAFs derived exosomal miR-22-3p was significantly associated with cisplatin resistance. Using various co-culture models, we showed the regulatory function of Rab27b and CAFs derived exosomal miR-22-3p, as well as the inhibitory effect of miR-22-3p on PTEN and ferroptosis. Experiments in vivo validated that CAFs derived exosomal miR-22-3p downregulated ferroptosis and promoted resistance to cisplatin. Overall, our findings suggest that targeting the Rab27b/exosomal miR-22-3p/PTEN/ferroptosis axis could be a promising therapeutic strategy for overcoming chemoresistance in osteosarcoma by providing critical insights into the role of exosome-mediated communication within the tumor microenvironment.