Doxorubicin (DOX) is a commonly used first-line anticancer drug that functions as a DNA topoisomerase II inhibitor. Its cytotoxic properties are mediated through the induction of DNA strand breaks or disruptions in RNA metabolism [
43]. Despite the advantages of doxorubicin, such as increased survival rates in breast cancer patients, the development of drug resistance is almost inevitable. Resistance to DOX has become a significant barrier to successful oncological treatment.
Exosomes containing miRNAs derived from drug-resistant breast cancer cells have the ability to traverse the tumor microenvironment and transmit drug resistance to neighboring sensitive cells by transferring specific miRNAs, which in turn alter gene expression within the sensitive cells [
44]. For example, the resistance to doxorubicin can be transmitted from resistant MCF-7 cells to normal MCF-7 cells through the exosome-mediated transfer of miR-222 [
45]. However, the exact mechanism of this transfer is still unknown. Through microarray analysis, 52 novel miRNAs with elevated expression levels in drug-resistant cells were identified. Bioinformatics studies of these miRNAs could help overcome chemoresistance in future breast cancer treatments [
46]. Subsequent research revealed that doxorubicin-resistant MCF-7 cells release exosomes carrying specific miRNAs (miR-100, miR-222, and miR-30a), which regulate the distribution of the cell cycle during intercellular transfer, decrease apoptosis induced by drug treatment, and confer doxorubicin resistance to sensitive MCF-7 cells [
47]. Moreover, miR-770 present in tumor-derived exosomes can be transferred to macrophages. This transfer leads to the regulation of DNA repair and the activation of M1 polarization, ultimately inhibiting chemoresistance in breast cancer cells. MiR-770 acts as a potential tumor suppressor by targeting STMN1 to downregulate it. This regulation of STMN1 in turn affects apoptosis, epithelial-mesenchymal transition, metastasis, and chemoresistance to doxorubicin in triple-negative breast cancer, thereby altering the tumor microenvironment [
48]. Therefore, miR-770 may serve as a new prognostic marker and provide new insights to understand the underlying mechanisms of chemotherapy resistance and metastasis. Furthermore, recent studies have shown that the exosome miR-181b-5p secreted by DOX-resistant cells can be taken up by recipient cells to induce DOX resistance by down-regulating BCLAF1 expression and subsequent p53/p21-mediated evasion of senescence [
49]. This suggests that the development of inhibitors targeting miR-181b-5p has therapeutic potential in the treatment of DOX-resistant BC patients.