Targeting the RUNX2–TGF-β regulatory circuit to overcome cancer stem cell-mediated chemoresistance in triple-negative breast cancer: mechanisms, therapeutic opportunities, and translational challenges

Background. Chemoresistance in triple-negative breast cancer (TNBC) remains a critical driver of relapse and metastasis. Current explanatory models—EMT reversibility, the absence of upstream CSC drivers, TGF-β pleiotropy, and fragmented RUNX2 functions—exist in isolation, lacking a unified framework. Main body This review proposes the RUNX2-TGF-β positive feedback loop as a working hypothesis for a regulatory node that integrates these mechanisms. In this proposed circuit, TGF-β is postulated to activate RUNX2, which in turn amplifies TGF-β signaling, forming a self-reinforcing loop that is proposed to sustain CSC stemness, plasticity, metabolic adaptation, and drug tolerance. We synthesize the molecular evidence for this circuit, propose a candidate causal chain in chemoresistance, and critically evaluate cross-cancer evidence while distinguishing it from TNBC-specific findings. We then critically analyze why most targeted strategies succeed preclinically yet fail clinically, covering TGF-β inhibitor toxicity, RUNX2 “undruggability,” weak natural compound evidence, and the model-to-clinic gap. Conclusion Given the limited direct causal evidence in TNBC, the RUNX2-TGF-β circuit is presented here as a working hypothesis rather than an established resistance mechanism. We propose a translational validation roadmap and highlight key unresolved questions. Unlike previous reviews, this work explicitly grades the evidence for each link in the circuit and designs a falsifiable experiment to test whether circuit disruption reverses established chemoresistance.