Nanoscale re-structuring of the immune synapse with an engager enhances NK cell function
Author(s)
Type
Journal Article
Abstract
Engagers are antibody-based therapies which bind immune cell receptors and a target cell ligand. Next-gen engagers typically bind two activating receptors, but the effect of this on immune synapse formation and signaling is unknown. Here, we coligated activating receptors CD16a and NKG2D on natural killer (NK) cells with a CD33-binding anti-acute myeloid leukemia (AML) engager. Superresolution microscopy revealed that coligating CD16a and NKG2D with a single molecule triggered their nanoscale coclustering. This enhanced phosphorylation of CD3ζ, ZAP70, and SLP-76 which augmented secretion of IFN-γ and TNF-α, by NK cells from healthy donors and AML patients. Thus, in addition to connecting immune cells to target cells, the clinical promise of engagers results from their ability to manipulate the nanoscale architecture of the immune synapse.
Date Issued
2025-09-23
Date Acceptance
2025-08-20
Citation
Proceedings of the National Academy of Sciences of USA, 2025, 122 (38)
ISSN
0027-8424
Publisher
National Academy of Sciences
Journal / Book Title
Proceedings of the National Academy of Sciences of USA
Volume
122
Issue
38
Copyright Statement
© 2025 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Publication Status
Published
Article Number
e2507336122
Date Publish Online
2025-09-18