Redirecting cytotoxic lymphocytes to breast cancer tumors via metabolite-sensing receptors.

ABSTRACT: Insufficient infiltration of cytotoxic lymphocytes to solid tumors limits the efficacy of immunotherapies and cell therapies. Here, we report a programmable mechanism to mobilize Natural Killer (NK) and T cells to breast cancer tumors by engineering these cells to express orphan and metabolite-sensing G protein-coupled receptors (GPCRs). First, in vivo and in vitro CRISPR activation screens in NK-92 cells identified GPR183, GPR84, GPR34, GPR18, FPR3, and LPAR2 as top enhancers of both tumor infiltration and chemotaxis to breast cancer. These genes equip NK and T cells with the ability to sense and migrate to chemoattracting metabolites such as 7α,25-dihydroxycholesterol and other factors released from breast cancer. Based on Perturb-seq and functio

SUBMITTER: Kim YM 

PROVIDER: S-EPMC11974742 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature