Guidong Chen, Silei Wang, Fanchen Wang, Chenju Yang, Rui Zhang, Pengpeng Liu, Junya Ning, Shuyu Wang, Feihe Ma, Linlin Xu, Linqi Shi, Jinpu Yu
Breast cancer is one the most common cancers in women, with 70% of cases being hormone receptor-positive (HR+), and recurrence and distant metastasis are the leading causes of mortality. Myeloid-derived suppressor cells (MDSCs) are one of the main immunosuppressive cell subsets within the tumor microenvironment (TME) and we previously demonstrated that PIK3CA mutation could induce immune evasion by recruiting MDSCs in breast cancer. However, the direct role of MDSCs in regulating breast cancer cells to promote tumor progression remains unclear. In this study, we found that MDSCs co-incubation enhanced the migration and invasion of HR+ breast cancer cells. Additionally, exosomal miR-155-5p from MDSCs was shown to downregulate SIRT1 expression in breast cancer cells, thereby promoting epithelial-mesenchymal transition. To address this, we developed a TME-responsive polymeric micelle co-delivering alpelisib (a pan-PI3K inhibitor) and cobomarsen (a miR-155-5p inhibitor) for targeted therapy. The poly(β-amino ester) backbone encapsulated hydrophobic alpelisib for acid-triggered release, while hydrophobized cobomarsen was integrated into the micellar core to improve stability and intracellular delivery. This dual-targeting strategy effectively suppressed PIK3CA-mutated tumor growth and epithelial-mesenchymal transition. These findings reveal the role of MDSC-driven metastatic potential via the exosomal miR-155-5p/SIRT1 axis in HR+ breast cancer and present a novel nanotherapeutic approach for precision intervention. A tumor microenvironment-responsive polymeric micelle co-delivering alpelisib and cobomarsen suppresses PIK3CA-mutated HR+ breast cancer progression by simultaneously blocking PI3K signaling and MDSC-derived exosomal miR-155-5p/SIRT1 axis-mediated epithelial-mesenchymal transition, offering a promising nanotherapeutic intervention for HR+ breast cancer.