Stanford University researchers identified cell surface ligands that control how tumor cells respond to natural killer cell killing, according to a study published in Nature Communications on August 6, 2026. Natural killer cell immunotherapies can eliminate cancer cells without requiring antigen presentation, providing potential off-the-shelf utility, but the molecular mechanisms controlling tumor susceptibility to this cytotoxicity have remained incompletely understood.
The research team applied a CRISPR activation screening platform focused on the surfaceome across human and murine cancer cell lines co-cultured with natural killer cells. This gain-of-function approach allowed the investigators to track both established and novel surface factors that modulate immune cell cytotoxicity.
Screens identified the established factor CD43 alongside previously uncharacterized regulators, specifically CD44, PDPN, and Siglec-1, also known as CD169. The authors validated these targets using orthogonal methods, confirming that disrupting the molecules altered natural killer cell killing susceptibility both in vitro and across humanized mouse models.
Mechanistic analyses revealed that CD43 drives tumor resistance to natural killer cells independently of its proposed interaction with Siglec-7. Applying targeted interventions against CD43 on natural killer cells or CAR T cells substantially increased cytotoxic destruction of leukemia cells.
Lead authors Ravi K. Dinesh, Xiaotong Wang, and Imran A. Mohammad conducted the study alongside co-authors Pari Gunasekaran, Kostas Stiklioraitis, Anirudh Rao, Jeremy R. Villafuerte, Rogelio A. Hernandez-Lopez, John B. Sunwoo, and Le Cong. The research received backing from National Institutes of Health grants 1R35HG011316, 1R01GM141627, R35DE030054, and R35GM155437.
