Engineering NK and T cells with metabolite-sensing receptors to target solid tumors.

Natural killer (NK) cells and T cells need to infiltrate solid tumors to eradicate them. Here we show programmable mechanisms that can mobilize NK and T cells to solid tumors using metabolite-sensing receptors. In vivo and in vitro CRISPR activation screens using NK-92 cells identified GPR183, GPR84, GPR34 and GPR18 as top enhancers of infiltration and chemotaxis to breast and ovarian cancers. While endogenously expressed in restricted cellular contexts, expressing these receptors in NK and T cells drives migration to factors released by cancer cells and alters the NK cell transcriptome in a ligand-dependent manner. Expressing GPR183 in NK, chimeric antigen receptor (CAR) NK and CAR T cells increased tumor infiltration and control. Likewise, expressing GPR183 in mouse T cells increased tumor eradication in immunocompetent mice. These data show that metabolite sensing can be rewired to obtain biochemically guided spatially targeted cells, creating new possibilities for therapeutic intervention.