Triple-negative breast cancer (TNBC) is characterized by marked clinical and molecular heterogeneity, which underlies the limited success of currently available targeted therapies and results in most patients relying on cytotoxic chemotherapy. This therapeutic gap underscores the pressing need for novel therapeutic approaches, in which non-coding RNAs (ncRNAs) have emerged as promising candidates. In this systematic review, 35 pre-clinical studies published between 2020 and 2025 were analyzed to evaluate the therapeutic potential of targeting ncRNAs in TNBC, including miRNAs, lncRNAs, and circRNAs. The original articles employed in vivo tumor models to assess the therapeutic response of ncRNA expression modulation, using miRNA mimics, antagomiRs, ASOs, shRNAs, and siRNAs integrated into advanced targeted delivery systems, such as nanoparticles and exosomes. According to the selected studies, 28 specific ncRNAs were identified as actionable molecular targets. Modulation of these molecules consistently resulted in tumor growth suppression, metastasis inhibition, and restoration of sensitivity to standard chemotherapeutic agents. Collectively, the pre-clinical evidence presented in these studies positions ncRNA-based therapies as innovative, promising, and potentially effective strategies for advancing TNBC treatment.
Scaratti et al. (Sun,) studied this question.