Switching circuits: Modulating NK cell response to TGF-β using novel receptors

ABSTRACT Engineered natural killer (NK) cells offer a promising treatment strategy for multiple therapeutic areas, yet tuning cell function to diverse environmental and inhibitory contexts remains a significant challenge. An attractive strategy for functional rescue in the presence of inhibitory ligands is the use of switch receptors, surface-expressed chimeric receptors that convert an external inhibitory cue into an intracellular activation signal. Here, we discover novel engineered switch receptors in NK cells that are responsive to TGF-β, a soluble inhibitory factor present in many therapeutic contexts. Through a pooled screen of an 11,131 member library, we identified multiple novel signaling endodomains and endodomain combinations that improve both the acute cytotoxicity and persistence of NK cells in the presence of TGF-β, demonstrating a novel and flexible approach to switch receptor discovery.