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

ABSTRACT 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 [ ⁶⁸ Ga]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, [ ⁶⁸ Ga]Ga‐Pentixafor PET imaging can guide decision‐making for AMD3100 therapy, paving the way for further clinical translation.