Targeting the CXCR4/CXCL12 Axis to Overcome Drug Resistance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant forms. TNBC is an aggressive and therapeutically resistant subtype of breast cancer, marked by the absence of estrogen, progesterone, and HER2 receptors. The lack of defined molecular targets significantly limits treatment options and contributes to high recurrence rates. Among the key pathways involved in TNBC progression and resistance, the CXCR4/CXCL12 chemokine axis has emerged as a critical player. CXCR4, a G-protein-coupled receptor, binds specifically to its ligand CXCL12, promoting tumour cell proliferation, metastasis, immune evasion, and stromal remodelling. Its overexpression is frequently associated with poor prognosis, disease progression, and resistance to conventional therapies in TNBC. This review explores how the chemokine receptor type 4 (CXCR4/CXCL12) axis facilitates drug resistance through mechanisms such as epithelial–mesenchymal transition (EMT), cancer stemness, and microenvironmental interactions. Notably, CXCR4 antagonists like plerixafor, balixafortide, and POL5551 have shown encouraging preclinical and clinical results, particularly when combined with chemotherapy or immunotherapy. Additionally, innovative strategies, including radiopharmaceuticals, peptide inhibitors, and nanotechnology-based delivery platforms, offer expanded therapeutic avenues. Despite persistent challenges such as tumour heterogeneity and potential toxicity, growing clinical evidence supports the translational relevance of this axis. This manuscript provides an in-depth analysis of CXCR4/CXCL12-mediated drug resistance in TNBC and evaluates current and emerging therapeutic interventions.