CEBPA enhances tumor radiosensitivity through ferroptosis and associates with tumor immune microenvironment

Abstract Radiotherapy has shown measurable efficacy with objective response rate and prolonged progression-free survival (PFS) in patients with breast cancer (BC). However, radioresistance is still a major challenge in BC radiotherapy, leading to limited clinical application and treatment failure. Therefore, elucidating the underlying mechanisms and developing effective strategies to enhance the radiosensitivity is of clinical importance. In the present study, we demonstratedCCAAT enhancer-binding protein alpha (CEBPA) as a specific marker for predicting the efficacy of radiotherapy in BC patients. CEBPA enhanced radiotherapeutic sensitivity of BC by increasing the apoptosis both in vitro and in vivo. Mechanistically, CEBPA executed radio-sensitizing function in BC by promoting ferroptosis through negatively regulating the nuclear factor E2-related factor 2 (Nrf2) pathway genes. Furthermore, high expression of CEBPA was positively correlated with the infiltration of cytotoxic immune cells in BC microenvironment. In summary, our work revealed CEBPA as a critical regulator to enhance radiosensitivity, induce ferroptosis, as well as modulate tumor immune microenvironment in BC. Induction of CEBPA or ferroptosis with specific inducers or modulation of tumor immune microenvironment would be potential sensitizing therapeutic strategies in BC.