Fibroblast activation protein promotes natural killer cell invasion and tumor infiltration

Natural killer (NK) cells play essential roles in immunity, but their limited infiltration into solid tumors restricts their therapeutic potential. Here, we identify fibroblast activation protein (FAP), previously thought to be largely fibroblast-restricted, as a novel surface-expressed protease on human NK cells. Using genetic knockout, pharmacologic inhibition, and overexpression approaches, we demonstrate that FAP regulates NK cell migration, matrix invasion, and tumor infiltration in vitro and in vivo. FAP overexpression enhanced NK cell invasion through extracellular matrices, improved infiltration into tumor spheroids, and increased tumor cell lysis. In mouse xenograft models, FAP-overexpressing NK cells infiltrated tumors more effectively and significantly reduced tumor burden compared to wild-type NK cells. These findings reveal a previously unrecognized role of FAP in NK cell biology and suggest that engineering NK cells to enhance proteolytic migration may improve the efficacy of NK cell-based cancer immunotherapies.

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Publication Details

Journal
The Journal of Immunology
Published
2025-10-28
DOI
https://doi.org/10.1093/jimmun/vkaf279
Primary Topic
Peptidase Inhibition and Analysis
Type
article
Field-Weighted Citation Impact
0.00
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article

Fibroblast activation protein promotes natural killer cell invasion and tumor infiltration

Eric Glasgow, Gray W. Pearson, Emily Margaret Mace, Nuan Wang et al.
The Journal of Immunology
Peptidase Inhibition and Analysis
article

Fibroblast activation protein promotes natural killer cell invasion and tumor infiltration

Eric Glasgow, Gray W. Pearson, Emily Margaret Mace, Nuan Wang, Annabel Lee, Apsra Nasir, Elana J. Fertig, Emily F. Davis-Marcisak, Pieter Van der Veken, Louis M. Weiner, Marwa M. Afifi, Shira E. Eisman, Allison A. Fitzgerald, Sandra A. Jablonski, Rachael Maynard
article en

Abstract

Natural killer (NK) cells play essential roles in immunity, but their limited infiltration into solid tumors restricts their therapeutic potential. Here, we identify fibroblast activation protein (FAP), previously thought to be largely fibroblast-restricted, as a novel surface-expressed protease on human NK cells. Using genetic knockout, pharmacologic inhibition, and overexpression approaches, we demonstrate that FAP regulates NK cell migration, matrix invasion, and tumor infiltration in vitro and in vivo. FAP overexpression enhanced NK cell invasion through extracellular matrices, improved infiltration into tumor spheroids, and increased tumor cell lysis. In mouse xenograft models, FAP-overexpressing NK cells infiltrated tumors more effectively and significantly reduced tumor burden compared to wild-type NK cells. These findings reveal a previously unrecognized role of FAP in NK cell biology and suggest that engineering NK cells to enhance proteolytic migration may improve the efficacy of NK cell-based cancer immunotherapies.

The Journal of ImmunologyVol. 215(2)
Human Genome Sciences (United States) (US), University of Maryland, Baltimore (US), Johns Hopkins University (US), University of Antwerp (BE), Georgetown University (US), Columbia University Irving Medical Center (US), Georgetown University Medical Center (US), Columbia University (US)
Openalex Percentile: Top 58%
Peptidase Inhibition and Analysis
DOISourceOpenAlex
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