Mapping CSC-Mediated Ovarian Cancer Chemoresistance via CXCR4-PET to Guide Precision Cisplatin Re-Sensitization Therapy

Therapy targeting Cancer Stem Cells (CSCs) has been proposed as a promising strategy to reduce chemoresistance and relapse risks in ovarian Cancer (OC) patients. However, the lack of targetable markers impedes research progress. Here, we demonstrate that CXC motif Chemokine Receptor 4 (CXCR4) may be a targetable functional marker of ovarian CSCs and propose a new translational model incorporating targeted imaging and CXCR4 blockade in CXCR4⁺ tumors. Expression profile analysis of chemoresistant CSC-like ovarian Cancer cells highlighted that CXCR4 functions as a potential stemness marker. CXCR4⁺ ovarian Cancer cells exhibited high self-renewal capacity in vitro and in vivo, and an association with chemoresistance. CXCR4 Inhibitor AMD3100 significantly impaired the self-renewal ability of CSC-like ovarian Cancer cells and enhanced their sensitivity to cisplatin. CXCR4-targeted [⁶⁸Ga]Ga-Pentixafor was highly specific in delineating CXCR4-high cell line-derived xenografts and patient-derived xenografts (PDXs) via positron emission tomography (PET) imaging, with precise tumor-targeting and persistent retention. A combination of AMD3100 and CDDP exerted an excellent antitumor effect in CXCR4-high PDXs, but not in CXCR4-low PDXs. These results suggest that CXCR4 may represent a functional CSC marker associated with chemoresistance. Moreover, [⁶⁸Ga]Ga-Pentixafor PET imaging can guide decision-making for AMD3100 therapy, paving the way for further clinical translation.