Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors: Frontiers in Immunology

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Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors. © Copyright © 2020 Melaiu, Lucarini, Cifaldi and Fruci.
Original languageEnglish
JournalFront. Immunol.
Publication statusPublished - 2020


  • adoptive transfer of NK and CAR-NK cells
  • cancer stem cells
  • cellular metabolism
  • hypoxia
  • immune checkpoint inhibitors
  • natural killer cells
  • solid tumors
  • tumor microenvironment
  • atezolizumab
  • avelumab
  • bortezomib
  • checkpoint kinase inhibitor
  • dostarlimab
  • durvalumab
  • interleukin 15
  • monoclonal antibody
  • pembrolizumab
  • sintilimab
  • spartalizumab
  • ticilimumab
  • toripalimab
  • trastuzumab
  • adaptive immunity
  • animal cell
  • animal experiment
  • animal model
  • biological functions
  • cancer infiltration
  • cancer model
  • cancer prognosis
  • cancer resistance
  • cancer stem cell
  • cancer susceptibility
  • cell activation
  • cell metabolism
  • cell proliferation
  • controlled study
  • cytokine production
  • cytotoxicity
  • gene knockout
  • immunosuppressive treatment
  • immunosurveillance
  • innate immunity
  • lymphocyte
  • mouse
  • natural killer cell
  • nonhuman
  • phenotype
  • Review
  • solid malignant neoplasm
  • survival analysis
  • tumor growth
  • upregulation
  • animal
  • genetics
  • human
  • immunology
  • neoplasm
  • Animals
  • Humans
  • Immunity, Innate
  • Killer Cells, Natural
  • Neoplasms
  • Tumor Microenvironment


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