NK cell exhaustion in the tumor microenvironment

Front Immunol. 2023 Nov 2:14:1303605. doi: 10.3389/fimmu.2023.1303605. eCollection 2023.

Abstract

Natural killer (NK) cells kill mutant cells through death receptors and cytotoxic granules, playing an essential role in controlling cancer progression. However, in the tumor microenvironment (TME), NK cells frequently exhibit an exhausted status, which impairs their immunosurveillance function and contributes to tumor immune evasion. Emerging studies are ongoing to reveal the properties and mechanisms of NK cell exhaustion in the TME. In this review, we will briefly introduce the maturation, localization, homeostasis, and cytotoxicity of NK cells. We will then summarize the current understanding of the main mechanisms underlying NK cell exhaustion in the TME in four aspects: dysregulation of inhibitory and activating signaling, tumor cell-derived factors, immunosuppressive cells, and metabolism and exhaustion. We will also discuss the therapeutic approaches currently being developed to reverse NK cell exhaustion and enhance NK cell cytotoxicity in the TME.

Keywords: NK cell; cancer; exhaustion; immunotherapy; tumor microenvironment.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents*
  • Humans
  • Killer Cells, Natural
  • Neoplasms*
  • Tumor Escape
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by the Multi-Year Research Grant of the University of Macau (File no. MYRG2020-00121-FHS and MYRG2022-00025-FHS), the Science and Technology Development Fund (FDCT) of Macao (File no. 0147/2020/A3, 044/2021/APD, and 0004/2021/AKP) and Ministry of Education Frontiers Science Centre for Precision Oncology (File no. SP2021-00001-FSCPO and SP2023-00001-FSCPO).