Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, which remains the most prevalent malignancy worldwide. Currently, TNBC lacks specific therapeutic targets. Histone deacetylases (HDACs) are aberrantly overexpressed in various tumors, including TNBC; consequently, HDAC inhibitors have demonstrated anti-tumor efficacy and the potential to reverse drug resistance. Chidamide is the first HDAC inhibitor globally approved for the clinical treatment of solid tumors. However, its clinical efficacy in TNBC patients remains unclear or controversial, primarily due to the absence of predictive biomarkers. Moreover, the development of drug resistance and toxicity at high concentrations have further limited its clinical application. Hence, tracing the evolutionary trajectory of proteome profiles in cancer cells under prolonged drug exposure was performed to explore potential vulnerabilities induced by a series of Chidamide treatments, as well as corresponding combination strategies.