Cancer-associated transporters: Molecular drivers and drug delivery gateways.

Abstract

Membrane transporters are critical regulators of cellular homeostasis, mediating the uptake and efflux of nutrients, ions, and drugs. In cancer, their expression is frequently reprogrammed to support enhanced growth, survival, metabolic rewiring, invasiveness, and therapy resistance. Among these several solute carrier (SLC) transporters such as glucose transporters (GLUTs), monocarboxylate transporters (MCTs), and the sodium/iodine symporter (NIS) also facilitate selective delivery of radiopharmaceuticals, making them attractive therapeutic targets. The tumor suppressor p53 known for its central role in genome stability and apoptosis, also regulates a broad spectrum of membrane transporters. However, oncogenic mutations or structural conversion into amyloids can disrupt this regulatory network, leading to altered transporter expression and multidrug resistance. Despite growing interest, the transcriptional and post-transcriptional control of transporters by wt, mutant, and amyloid forms of p53 remains underexplored. In this review, we systematically characterize the p53-mediated regulation of diverse transporter classes involved in the transport of sugar, amino acids, metal ions, lipids along with ABC transporter functions and multidrug resistance. We highlight how cancer cells exploit transporters such as P-glycoprotein (P-gp), LAT1, GLUT1, MCTs, and NIS for metabolic advantage and survival. We also examine therapeutic strategies aimed at modulating transporter function using CRISPR/Cas9, small-molecule inhibitors, siRNA, and nanoparticle-based co-delivery systems. In particular, LAT1 inhibition demonstrates potential to starve tumors of essential nutrients. Ultimately, we propose that dual targeting of p53 aberrations and membrane transporters through synthetic biology and precision delivery approaches could restore chemosensitivity and suppress tumor progression, offering promising avenues for personalized cancer therapy.