Spatiotemporal delivery of immune-synapse-stabilizing NK cells for postoperative tumor therapy

Abstract

Natural killer (NK) cells eliminate target cells by forming an immunological synapse (IS). Here, we equip NK cells with multivalent galectin-3 binding polymers that resemble prehensile “arms” to mechanically reinforce the NK-to-target tumor cell connection. These armed NK cells (a-NKs) stabilize the IS by extending average duration of cell-cell contacts. This enforced proximity drives substantial IS remodeling that enhances NK cell degranulation and cytotoxicity, thereby converting transient “kiss-and-run” interactions into a lethal “kiss of death”. In the context of postoperative therapy for breast cancer in female mice, a semi-spike patch inserted in resection cavity is designed for immediate delivery of anti-inflammatory dexamethasone agent and sustainable release of a-NKs. This ensures timely immunomodulation precedes a-NK deployment. Given a-NKs’ capacity to orchestrate T cell responses beyond direct cytotoxicity, this platform, integrating IS-stabilizing paradigm with a localized spatiotemporal delivery, coordinates adoptive a-NK therapy and adaptive immune activation to persistently act against residual tumors post-surgery. Here, Li and colleagues report that arming NK cells with surface-anchored, multivalent galectin-3 binding polymers prolongs NK-to-tumor target cell contact and enhances NK cytotoxicity; as well, authors describe that a semi-spike patch for spatiotemporal delivery of armed NK cells in the resection cavity prevents tumor recurrence post-surgery.