The current therapeutic approaches for triple-negative breast cancer (TNBC) have not yielded the same clinical outcomes as the ones utilized in other breast cancer subtypes. A major reason for this is the lack of targeted treatment options that synergize with current treatment modalities, and limited exploration into the biological associations of therapy resistance and tumor progression. Radiation therapy significantly reduces locoregional recurrence rates for breast cancer patients, and the recent developments in image-based guidance improve efficacy and mitigate toxicity. However, the biological underpinnings of radiation resistance in TNBC are rarely studied. My work explored factors responsible for resistance to radiotherapy and it also uncovered the radiation-induced signaling cascades that impact metastasis of TNBC. The first project of my thesis explores the role of inhibiting the binding of vascular endothelial growth factor (VEGF) to neuropilin-2 (NRP2) signaling to enhance the radiosensitivity of TNBC. Given the role of NRP2 in activating cancer stem cell (CSC) properties such as self-renewal and chemoresistance, I was intrigued by my data demonstrating that combining a function blocking antibody of VEGF/NRP2 with radiotherapy significantly decreases the survival of TNBC cell lines, organoids, and patient-derived xenografts (PDXs) compared to radiotherapy alone. I later determined that this sensitivity is a product of decreased nitric oxide synthase 2 (NOS2) expression in NRP2-expressing cells. The nitric oxide hub mediated by NRP2 expressing cells is a critical component of nuclear factor erythroid 2-related factor (Nrf2) activation and the expression of its antioxidant response elements. Therefore, the VEGF/NRP2 axis can mitigate the radiation-induced oxidative stress on tumor cells. The second aspect of my thesis uncovers the role of RNA metabolism in radioresistant TNBC that mediates enhanced metastasis compared to radiosensitive TNBC. Specifically, I identified the role of the RNA binding protein heterogenous nuclear ribonucleoprotein L (HNRNPL) in mediating the formation of circular RNAs (circRNAs) that sponge the let-7 family of microRNAs (miRNAs). Overall, I implicated HNRNPL-derived circRNAs as important mediators of the stability of integrin b3 (ITGb3) mRNA, which promotes metastasis. Interestingly, this pathway is a byproduct of enhanced Nrf2 activation that can induce HNRNPL expression in TNBC. Interestingly, the subpopulation of cells within TNBC that have the capacity to initiate antioxidant pathways are the ones capable of surviving radiation therapy, as well as execute cellular programs that mediate metastasis. In summary, my thesis provides a targeted therapy that can be utilized in TNBC to enhance its radiosensitivity, and I identify a novel mechanism within radioresistant TNBC that promotes its metastatic capacity.