Stage-Specific Regulation of Ubiquitination Modifications and Prospects for Targeted Therapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor clinical outcomes. Owing to the absence of estrogen receptors, progesterone receptors, and Human Epidermal Growth Factor Receptor 2 (HER2) expression, TNBC shows limited responsiveness to conventional endocrine and targeted therapies. This subtype exhibits strong heterogeneity, a high propensity for metastasis, and a tendency to develop acquired drug resistance. Its survival and progression largely rely on non-classical signaling pathways, including Epidermal growth factor receptor (EGFR), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), and Notch, which collectively impose substantial challenges to clinical management. In recent years, protein post-translational modifications-particularly ubiquitination and ubiquitin-like modifications-have emerged as key mechanisms governing TNBC malignant progression. This review systematically summarizes the stage-specific regulatory roles of ubiquitination during TNBC initiation, progression, and therapeutic resistance. These mechanisms include modulation of tumor stemness, epithelial-mesenchymal transition, DNA damage repair, ferroptosis, and immune evasion through the regulation of critical proteins such as Toll-like receptor 4/Nuclear factor kappa-B (TLR4/NF-κB), Twist family bHLH transcription factor 1 (TWIST1), Poly (ADP-Ribose) Polymerase 1 (PARP1), Programmed death-ligand 1 (PD-L1), and Glutathione Peroxidase 4 (GPX4). In addition, ubiquitin-like modifications (including small ubiquitin-like modifier (SUMOylation), Neural precursor cell expressed developmentally downregulated protein 8 (NEDDylation), and Interferon-stimulated gene (ISGylation)) function synergistically in maintaining genome stability, transcriptional regulation, and immunological processes. Furthermore, this review highlights the translational potential of targeting ubiquitination pathways in TNBC, covering the applications, advantages, and limitations of immune checkpoint inhibitors, Poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and combination treatment strategies. Finally, it outlines future research directions, such as developing a TNBC-specific ubiquitinome landscape, creating highly selective E3 ligase or deubiquitinase inhibitors, and integrating multi-omics with artificial intelligence technologies. These advances are expected to provide a theoretical foundation and translational insights for precision interventions targeting protein homeostasis in TNBC.