Reprogramming CAR-T cells: Targeting SLC transporters for tumor microenvironment adaptation

Abstract

T cell activation, triggered by antigen recognition via the T cell receptor, initiates crucial physiological changes necessary for proliferation and survival. This process encompasses epigenetic modifications that open chromatin for transcription factor binding, transcriptomic shifts activating key genes, and structural adaptations, including increased cell size and cytoskeletal changes. Activated T cells experience heightened metabolic demands, requiring efficient nutrient uptake primarily via Solute Carrier (SLC) transporters. These transporters, regulated by transcription factors such as c-Myc, HIF-1α, NF-κB, and mTORC1, optimize nutrient acquisition to support glycolysis and macromolecule synthesis. In the tumor microenvironment, however, aberrant tumor metabolism depletes nutrients and produces metabolites that impair T cell function and reduce the efficacy of adoptive cell therapies, which are not metabolically adapted to survive in such hostile conditions. Modulating SLC transporters presents a promising strategy to enhance chimeric antigen receptor T cell (CAR-T) effectiveness by improving their persistence and antitumor activity. Personalized approaches targeting SLC transporters, tailored to the metabolic profiles of specific tumor types, are crucial for maximizing the therapeutic potential of adoptive T cell therapies. This review explores the critical role of SLC transporters in CAR-T cell functionality and discusses strategies to optimize their expression and activity within the challenging TME.

Keywords: CAR-T cells; Immunotherapy; Solid tumors; Solute carrier transporters; Tumor metabolism; Tumor microenvironment.