Hypoxic tumor microenvironment: Destroyer of natural killer cell function

Abstract

In recent years, immunotherapy has made remarkable progress in treating certain tumors and hematological malignancies. However, the efficacy of natural killer (NK) cells, which are an important subset of innate lymphocytes used in anticancer immunotherapy, remains limited. Hypoxia, a critical characteristic of the tumor microenvironment (TME), is involved in tumor development and resistance to radiotherapy, chemotherapy, and immunotherapy. Moreover, hypoxia contributes to the impairment of NK cell function and may be a significant factor that limits their therapeutic effects. Targeted hypoxia therapy has emerged as a promising research area for enhancing the efficacy of NK cell therapy. Therefore, understanding how the hypoxic TME influences NK cell function is crucial for improving antitumor treatment outcomes.

Keywords: Hypoxia; NK cell; immunotherapy; tumor microenvironment.

Figure 1

Hypoxia affects malignant biological behavior and treatment resistance of tumors.

Figure 2

Impact of hypoxia on NK cell anticancer activity. (A) Hypoxia induces the resistance of tumor cells to NK cells, which can lead to the downregulation of MICA/MICB and ULBPs on the surface of tumor cells, the upregulation of PD-L1 and HLA-G expression, and the release of IL-10 to resist the killing of NK cells; (B) Hypoxia directly affects NK cell function, leading to the downregulation of activating receptor expression of NK cells and the decrease of IFN-γ, granzyme B, perforin secretion, and affecting the maturation and survival of NK cells; (C) Hypoxia inhibits NK cell function by affecting other components of TME, such as immunosuppressive cells (Treg cells, M2 tumor-associated macrophages, MDSCs, etc.), cytokines, receptors, and metabolic changes (such as lactic acid accumulation). NK, natural killer; MIC, major histocompatibility complex class I chain-related gene; ULBP, UL16-binding protein; PD-L1, programmed death-ligand 1; HLA, human leukocyte antigen; IFN-γ, interferon gamma; TME, tumor microenvironment; Treg, regulatory T; MDSC, myeloid-derived suppressor cell; NKG, natural killer cell group; HRE, hypoxia response element; HIF, hypoxia-inducible factor; PD-1, programmed death 1; TAM, tumor-associated macrophages; TGF-β, transforming growth factor β; MCP1, monocyte chemoattractant protein-1; IL, interleukin; KIR, killer immunoglobulin-like receptor; ATP, adenosine triphosphate.