Triple-negative breast cancer (TNBC) is a subtype of breast cancer known for the poor prognosis due to its strong invasiveness, high recurrence rate, and lack of effective treatment. Therefore, there is an urgent need to find targeted therapy for TNBC. Cathepsin A (CTSA) is an acidic serine carboxypeptidase that is highly expressed in various tumor tissues. However, the role and molecular mechanism of CTSA in TNBC are still unclear. This study found that the expression of CTSA was upregulated, and the high expression of CTSA was positively correlated with the poor prognosis of TNBC. The results further showed that knocking down CTSA inhibited the proliferation, invasion, and colony formation of TNBC cells, improved drug sensitivity of cells, and inhibited the progression of TNBC. Mechanistically, CTSA inhibited the ubiquitination and degradation of the promyelocytic leukemia protein (PML) protein by blocking the interaction between PML and its E3 ubiquitin ligase RNF4, thus maintaining the stability of PML nuclear bodies (PML-NBs). The inhibitor of CTSA had a positive therapeutic effect on inhibiting the characteristics of TNBC stem cells. In conclusion, this study demonstrates that inhibiting CTSA to decrease the stability of PML protein may be a promising therapeutic strategy for TNBC. All animal experiments in this experiment were approved by the Ethics Committee of Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College (approval number: IMB-20240326D502).