PubMed · 42686754
Surfaceome CRISPR activation screening uncovers ligands regulating tumor sensitivity to NK cell killing.
Abstract
Natural killer (NK) cell-based immunotherapies are promising for cancer treatment due to their ability to eliminate cancer cells independently of antigen presentation and "off-the-shelf" utility. However, molecular determinants governing tumor susceptibility to NK cytotoxicity remain incompletely understood. Here we employ CRISPR activation (CRISPRa) screening to identify cancer cell surface regulators of NK killing. Using a surfaceome-focused library, we screen human and murine cancer cell lines co-cultured with NK cells, identifying known and novel ligands modulating NK cytotoxicity. Screens reveal established factors including CD43 and previously uncharacterized regulators CD44, PDPN, and Siglec-1/CD169. Validation with orthogonal approaches confirm that disruption of these factors alters NK killing susceptibility in vitro and in humanized mouse models. Mechanistically, we find that CD43-mediated NK resistance operates independently of its proposed interaction with Siglec-7, and that targeting CD43 on NK cells or CAR T cells substantially enhances cytotoxic activity against leukemia. These results establish gain-of-function surfaceome screening as a powerful tool for identifying therapeutic targets for NK cell-based immunotherapy.
Explore related subjects
Keep this discovery
Explore connections, maps & timelines
Ravi K Dinesh, Xiaotong Wang, Imran A Mohammad, Pari Gunasekaran, Kostas Stiklioraitis, Jeremy R Villafuerte, Anirudh Rao, Rogelio A Hernandez-Lopez, John B Sunwoo, Le Cong. 2026-08-06. Surfaceome CRISPR activation screening uncovers ligands regulating tumor sensitivity to NK cell killing.. https://doi.org/10.1038/s41467-026-76374-x
Cite the original work for its findings. Save a collection to share your selection of sources.