Triple-negative breast cancer remains an aggressive and biologically heterogeneous breast cancer subtype. Although the therapeutic landscape has expanded, durable disease control remains clinically challenging in many settings. Existing reviews often organize TNBC therapy by drug class or molecular subtype, which can obscure how treatment response is shaped by interacting biological layers. Here, we review current and emerging therapeutic strategies through a three-layer framework: tumor-cell-intrinsic vulnerabilities, the local immune and stromal microenvironment, and host-level systemic modifiers. We summarize established approaches, including chemotherapy, immune checkpoint blockade, antibody–drug conjugates and PARP inhibition in biomarker-defined settings, and distinguish them from maturing or exploratory strategies such as pathway-directed therapy, epigenetic modulation, anti-vascular combinations, regulated cell-death induction, cellular therapy, vaccines, microbiome-related interventions, liquid biopsy, AI-supported multiomics and adaptive trial designs. This framework integrates evidence level, disease stage, biomarker reliability and patient tolerance into treatment selection for TNBC precision therapy.
Zi-Xun Wang, Xi-Yu Liu, Yu-Xiao Wu et al.· Journal of Hematology & Onco...· 0 citations
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by a poor prognosis due to the lack of effective targeted therapies. While poly (ADP-ribose) polymerase (PARP) inhibitors benefit BRCA1/2-mutated TNBC, their efficacy in BRCA wild-type tumors remains limited. In this study, we uncover a critical role of zinc-finger protein 689 (ZNF689) in regulating homologous recombination (HR) repair in TNBC. Our findings reveal that in response to DNA damage, ZNF689 is phosphorylated by ATM and promotes NBS1 ubiquitination via E3 ligase SKP2, leading to the stabilization of the MRN complex and subsequent ATM activation, thereby facilitating HR repair. ZNF689 loss markedly enhances sensitivity to PARP inhibitors in TNBC, particularly when combined with paclitaxel. Furthermore, PARP inhibition upregulates PD-L1 expression in ZNF689-deficient TNBC cells through activation of the STING pathway. Notably, ZNF689 loss enhances the therapeutic efficacy of PARP inhibition plus anti-PD-L1 immunotherapy. Together, these findings suggest ZNF689 as a crucial regulator of HR repair and provide proof-of-concept for combining PARP inhibition and PD-L1 blockade in patients with ZNF689-low TNBC. While PARP inhibition is effective in patients with BRCA1/2-mutated triple-negative breast cancer (TNBC), its effect in BRCA wild-type TNBC is limited. Here, the authors identify a role of ZNF689 in regulation of homologous recombination repair via stabilization of the MRN complex, with ZNF689 deficiency conferring sensitivity to PARP inhibition, which upregulates PD-L1 expression and sensitizes tumors to combination therapy with anti-PD-L1 in TNBC.
