Regulation of Tumor-Immune Cell Communications via Enantioselectively Targeting SLC G-Quadruplexes

Compelling evidence shows that amino acids can influence tumor-immune cell communication. Their transfer across the plasma membrane involves multiple amino acid transporters within the solute carrier (SLC) family. Here, we present a new strategy to modulate SLC function by targeting the SLC G-quadruplexes (G4s). We first screen eight SLC genes in the promoter region and identify G4s, including one in the promoter region of glutamine transporter SLC38A2. Then, we design a CRISPR-chiral metallohelix system that selectively targets and stabilizes the SLC38A2 G4 in tumor cells, demonstrating evident enantioselectivity with the Λ-enantiomer being more effective. This leads to SLC38A2 downregulation, which shifts glutamine uptake from tumor cells to dendritic cells (DCs), thereby redirecting glutamine metabolism to activate DCs. Furthermore, we construct a CRISPR-DHX36 system to unwind the SLC38A2 G4 in DCs and upregulate SLC38A2 expression, further augmenting glutamine uptake to compete with tumor cells. The dual CRISPR system with the ability to "fold" and "unfold" the G4 motif in different cell types leads to a marked enhancement of CD8⁺ T cell activation and killing ability. Therefore, our work sheds new light on cancer immune regulation by modulating the metabolic communication between cancer cells and immune cells.