Critical role of tumor microenvironment in shaping NK cell functions: Implication of hypoxic stress

Meriem Hasmim, Yosra Messai, Linda Ziani, Jerome Thiery, Jean Henri Bouhris, Muhammad Zaeem Noman, Salem Chouaib*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

98 Citations (Scopus)


Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells, a key component of the innate immunity, are recognized as potent anticancer mediators. Extensive studies have been detailed on how NK cells get activated and recognize cancer cells. In contrast, few studies have been focused on how tumor microenvironment-mediated immunosubversion and immunoselection of tumor-resistant variants may impair NK cell function. Accumulating evidences indicate that several cell subsets (macrophages, myeloid-derived suppressive cells, T regulatory cells, dendritic cells, cancer-associated fibroblasts, and tumor cells), their secreted factors, as well as metabolic components (i.e., hypoxia) have immunosuppressive roles in the tumor microenvironment and are able to condition NK cells to become anergic. In this review, we will describe how NK cells react with different stromal cells in the tumor microenvironment. This will be followed by a discussion on the role of hypoxic stress in the regulation of NK cell functions. The aim of this review is to provide a better understanding of how the tumor microenvironment impairs NK cell functions, thereby limiting the use of NK cell-based therapy, and we will attempt to suggest more efficient tools to establish a more favorable tumor microenvironment to boost NK cell cytotoxicity and control tumor progression.

Original languageEnglish
Article number482
JournalFrontiers in Immunology
Issue numberSEP
Publication statusPublished - 2015
Externally publishedYes


  • HIF
  • Immune suppression
  • Microenvironment
  • Natural killer cells
  • Solid tumors


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