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. 2021 Sep 14;12:734551. doi: 10.3389/fimmu.2021.734551

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Copyright © 2021 Lee, Wong and Ding

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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TME factors suppress NK cell function. Tumour-intrinsic properties play a significant role in the downregulation of NK cytotoxicity through altering NK-cancer receptor-ligand interaction, which shifts the NK cell towards an inhibited/exhausted state. (1) The secretion of immunosuppressive cytokines modulates NK cell surface receptor expression. (2) Dysregulation of miRNA promotes the upregulation of inhibitory ligands and downregulation of activating ligands. (3) Upregulated post-translational modification processes (e.g., ubiquitination and SUMOylation) in tumour cells cause intracellular localisation of activating ligands, allowing tumour escape from NK cell recognition. (4) Chronic exposure to activating ligands on tumour cells promotes a feedback mechanism leading to endocytosis of NK cell activating receptors. (5) Altered cytoskeletal dynamics in tumours also contribute to tumour cell resistance to NK cell killing. Additionally, effective recognition of cancer by NK cells is hampered by (6) the multitude of other immune cells in the TME which not only downregulate NK function, but also aid tumour cells in evading NK cell recognition.