Spatial multi-omics guides ASCT2-targeted delivery of glycolysis inhibitor for cervical cancer suppression and chemoresistance reversal

Abstract

Introduction: Cervical carcinoma (CC) mortality remains high due to chemoresistance. Targeting glycolytic reprogramming is promising since CC cells depend on enhanced glycolysis for proliferation and chemoresistance. However, clinical translation faces two barriers: the lack of spatially resolved validation of glycolytic vulnerability in CC specimens, and absence of CC-specific delivery systems for lonidamine (LND), a potent glycolytic inhibitor with poor bioavailability and hepatotoxicity.

Objectives: Here, we aim to establish spatially resolved validation of tumor-associated glycolytic reprogramming and identify differentially enriched receptors within malignant regions in clinical CC specimens. Leveraging these findings, we will design a tumor-targeted nanoplatform for the precise delivery of a glycolytic inhibitor to CC cells, to achieve tumor suppression and reverse chemoresistance.

Methods: Spatial metabolomics and spatial transcriptomics analyses were employed to validate tumor-associated glycolytic reprogramming and identify specifically overexpressed receptors within malignant regions of clinical CC specimens.

Results: Through spatial multi-omics analysis, we demonstrated upregulated glycolysis in malignant regions of CC and identified solute carrier family 1 member 5 (ASCT2), a glutamine transporter, as a superior CC-specific surface marker compared to the pan-cancer nanocarrier targets like CD44. These findings were corroborated through multi-platform validation spanning single-cell RNA-seq dataset, TCGA cohorts, paired patient specimens, matched murine samples, and multiple CC cell lines. In this context, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression to enable CC-selective accumulation of LND. Our findings reveal that this nanoagonist significantly impedes CC growth by disrupting ATP supply and inducing ROS-mediated cellular damage. Moreover, this nanoagonist effectively reverses cisplatin (DDP)-induced chemoresistance in CC by inhibiting MRP2-mediated DDP efflux and blocking ribose-5-phosphate-mediated DNA repair.

Conclusion: By integrating spatial multi-omics with rational nanocarrier design, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression for tumor-selective accumulation of LND. Our findings revealed that this nanoagonist achieves significant CC suppression and chemoresistance reversal.

Keywords: ASCT2; Cervical Cancer; Chemoresistance Reversal; Glycolysis; HKⅡ; Spatial multi-omics analysis.