Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity

Isaac Dean, Colin Y C Lee, Zewen K Tuong, Zhi Li, Christopher A Tibbitt, Claire Willis, Fabrina Gaspal, Bethany C Kennedy, Veronika Matei-Rascu, Rémi Fiancette, Caroline Nordenvall, Ulrik Lindforss, Syed Murtuza Baker, Christian Stockmann, Veronika Sexl, Scott A Hammond, Simon J Dovedi, Jenny Mjösberg, Matthew R Hepworth, Gianluca CarlessoMenna R Clatworthy, David R Withers

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number683
JournalNature Communications
Issue number1
Publication statusPublished - 24 Jan 2024


  • Humans
  • Neoplasms
  • Gene Expression Profiling
  • Internship and Residency
  • Killer Cells, Natural
  • Transcriptome
  • Tumor Microenvironment


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