o:3072 Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity en 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 1552099 10.1038/s41467-024-44789-z 2024-06-05T07:52:43.711Z 44 yes 46 Isaac Dean University of Birmingham 0000-0002-4750-5335 Colin Y. C. Lee University of Cambridge / Wellcome Genome Campus person 0000-0001-8380-4917 Zewen K. Tuong University of Cambridge / Wellcome Genome Campus person 0000-0002-6735-6808 Zhi Li University of Birmingham person 0000-0002-0583-1116 Christopher A. Tibbitt Karolinska Institutet person Claire Willis University of Birmingham person Fabrina Gaspal University of Birmingham person Bethany C. Kennedy University of Birmingham person Veronika Matei-Rascu University of Birmingham person Rémi Fiancette University of Birmingham person 0000-0003-1531-9770 Caroline Nordenvall Karolinska University Hospital person Ulrik Lindforss Karolinska University Hospital person Syed Murtuza Baker University of Manchester person 0000-0002-6633-333X Christian Stockmann University of Zurich person Veronika Sexl University of Veterinary Medicine Vienna person 0000-0001-9363-0412 Scott A. Hammond AstraZeneca person 0000-0001-5800-4328 Simon J. Dovedi AstraZeneca person Jenny Mjösberg Karolinska Institutet / Karolinska University Hospital person 0000-0002-1119-0976 Matthew R. Hepworth University of Manchester person 0000-0002-9613-7858 Gianluca Carlesso AstraZeneca person Menna R. Clatworthy University of Cambridge / Wellcome Genome Campus person 0000-0002-3340-9828 David R. Withers University of Birmingham person 0000-0003-3757-7594 application/pdf 1452300 https://phaidra.vetmeduni.ac.at/o:3072 no yes 16 70 1552253 Nature Communications 18 15 1 Nature Portfolio 2024