Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, leading to poor prognosis and resistance to conventional therapies. Although taxanes, anthracyclines, and platinum-based drugs are widely used, treatment resistance and severe side effects remain major challenges. Flavonoids are natural bioactive compounds with promising anticancer activity through the modulation of oxidative stress, apoptosis, and multidrug resistance pathways. Among them, semi-synthetic chiral flavonoid derivatives (CDFs) have emerged as potential agents to overcome chemoresistance. Building on our previous findings demonstrating the cytotoxic activity of CDFs in TNBC cells, this project aims to investigate their molecular mechanisms using 3D spheroid models. We will optimize TNBC spheroid formation for compound evaluation, assess the cytotoxicity of a selected enantiomeric pair of CDFs, and evaluate their ability to sensitize cancer cells to doxorubicin. The effects observed in 2D and 3D models will be also compared.