Myeloid-derived suppressor cells mediate ferroptosis resistance in HR+/HER2- breast cancer via the ARID1A/AKR1C2 axis

Breast cancer is the most common malignancy in women, with approximately 70% of cases classified as the HR+/HER2- subtype. Recurrence and metastasis remain the leading causes of mortality in breast cancer patients. Resistance to ferroptosis has been recognized as a key factor in breast cancer progression, yet its relationship with myeloid-derived suppressor cells (MDSCs)-a critical component of the tumor microenvironment-has remained largely unexplored. In this study, we demonstrated that co-incubation of HR+/HER2- breast cancer cells with MDSCs significantly reduced their sensitivity to ferroptosis inducers and this process was closely associated with the downregulation of ARID1A expression. Further bioinformatic analysis and functional cellular experiments indicated that ARID1A loss drived the marked upregulation of the ferroptosis-suppressive gene AKR1C2 through epigenetic regulation. Overall, our findings reveal that MDSCs modulate AKR1C2 transcription by regulating ARID1A expression in HR+/HER2- breast cancer cells, thereby providing a promising strategy for the development of novel therapeutic targets against breast cancer.