Macrophage polarization regulated by the βTrCP-NF-κB inflammatory signaling pathway is required for valproic acid's dual role in breast tumor radiosensitivity and normal tissue radioprotection.

Radiotherapy (RT) is a widely used treatment modality for breast cancer, but its broad application is limited by the risk of adverse effects, such as the potential for the tumor to develop resistance to RT. Identifying strategies that enhance RT efficacy while minimizing adverse effects is of significant clinical importance. Valproic acid (VPA), an anti-epileptic drug, has shown promise in augmenting the efficacy of RT, though its underlying mechanisms remain unclear. We established in vitro co-culture systems and in vivo breast tumor models, and performed multiple molecular and cellular assays to investigate the immunological mechanism underlying VPA-mediated tumor radiosensitization. In this study, we demonstrated that VPA enhances the radiosensitivity of breast tumor by activating the βTrCP-NF-κB immune pathway, which reprograms tumor-associated macrophages (TAMs) into the M1 phenotype. VPA suppresses HDAC1/2 activity, which in turn upregulates βTrCP expression, accelerating ubiquitination and degradation of the NF-κB suppressor IκBα. In normal tissues, VPA suppresses the inflammatory response triggered by the βTrCP-NF-κB pathway. This bidirectional regulatory effect of VPA reveals a novel immunological mechanism for its application as a RT adjuvant, offering both enhanced tumor radiosensitivity and radioprotection of normal tissues.