Amino Acid Transporters in Glioblastoma: Implications for Diagnosis, Disease Monitoring, Therapeutic Targeting, and Drug Delivery.

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor with a median survival of 14-15 months even with standard multimodality treatments. The effectiveness of surgical resection, chemotherapy, and radiation therapy are limited by resistance mechanisms including tumor heterogeneity, immunosuppression, presence of stem-like cells, and inhibited drug delivery due to the blood-brain barrier (BBB). The BBB is composed of endothelial cells with tight junctions and selective transport systems, which prevent drug delivery to the tumor at therapeutic levels. Amino acid (AA) transporters have emerged as promising therapeutic targets for overcoming these limitations and enhancing GBM treatment. This review highlights the role of AA transporters in GBM, emphasizing their potential in enhancing targeted therapy, diagnosis, and disease monitoring. We summarize and discuss the 22 AA transporters which are upregulated in GBM, as well as those that demonstrate prognostic correlation. Among these, LAT1 (SLC7A5) has garnered the most attention for its role in drug delivery and imaging, while other transporters exhibit potential as diagnostic and therapeutic targets. Furthermore, nanoparticle technology has emerged as an innovative strategy to enhance targeted therapy through AA transporters. They can enable extended drug circulation, enhanced BBB penetration, and target-specific localization, offering synergistic therapeutic effects. This review emphasizes the importance of AA transporters as multifaceted tools for improving GBM treatment outcomes and the potential of combining AA transporter-targeted therapies with emerging technologies to address the limitations of current GBM management strategies.