https://phaidra.vetmeduni.ac.at/o:3072 Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity Dean, Isaac Isaac Dean 0000-0002-4750-5335 University of Birmingham Clatworthy, Menna R. Menna R. Clatworthy 0000-0002-3340-9828 University of Cambridge / Wellcome Genome Campus Withers, David R. David R. Withers 0000-0003-3757-7594 University of Birmingham Carlesso, Gianluca Gianluca Carlesso AstraZeneca Hepworth, Matthew R. Matthew R. Hepworth 0000-0002-9613-7858 University of Manchester Mjösberg, Jenny Jenny Mjösberg 0000-0002-1119-0976 Karolinska Institutet / Karolinska University Hospital Dovedi, Simon J. Simon J. Dovedi AstraZeneca Hammond, Scott A. Scott A. Hammond 0000-0001-5800-4328 AstraZeneca Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna Stockmann, Christian Christian Stockmann University of Zurich Baker, Syed Murtuza Syed Murtuza Baker 0000-0002-6633-333X University of Manchester Lindforss, Ulrik Ulrik Lindforss Karolinska University Hospital Nordenvall, Caroline Caroline Nordenvall Karolinska University Hospital Fiancette, Rémi Rémi Fiancette 0000-0003-1531-9770 University of Birmingham Matei-Rascu, Veronika Veronika Matei-Rascu University of Birmingham Kennedy, Bethany C. Bethany C. Kennedy University of Birmingham Gaspal, Fabrina Fabrina Gaspal University of Birmingham Willis, Claire Claire Willis University of Birmingham Tibbitt, Christopher A. Christopher A. Tibbitt Karolinska Institutet Li, Zhi Zhi Li 0000-0002-0583-1116 University of Birmingham Lee, Colin Y. C. Colin Y. C. Lee 0000-0001-8380-4917 University of Cambridge / Wellcome Genome Campus Tuong, Zewen K. Zewen K. Tuong 0000-0002-6735-6808 University of Cambridge / Wellcome Genome Campus Nature Portfolio text eng Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived. Innate Lymphoid-Cells; Cd8(+) T-Cells; Mouse Nk Cells; Growth-Factor; Adaptive Immunity; Dendritic Cells; In-Vivo; Expression; Programs; Differentiation http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3072/download 10.1038/s41467-024-44789-z https://phaidra.vetmeduni.ac.at/o:605 application/pdf Nature Communications 15(1) (2024) Nature Communications 15 1 1.39 MB 2024