TABLE 2.

The immune cells in TME: NK cells.

Cells	The research direction	Result	Reference
NK cells	immunotherapy	Sorafenib can promote the pro-inflammatory response of tumor-associated macrophages in HCC, and then activate the anti-tumor NK cell response through the cytokine and NF-κB pathway.	Sprinzl et al. (2013)
NK cells	The immune mechanism	NK cell activator Poly (I:C) promotes HCC in HBs-Tg mice. Poly (I:C) induces liver inflammation and liver cell damage in HBs-Tg mice. The increase of hepatocyte EMT depends on the presence of NK cells in HBs-Tg mice. IFN-γ derived from NK cells plays a key role in the development of HCC in HBs-Tg mice.	Chen et al. (2019)
NK cells	The immune mechanism	The phenotype of peripheral blood NK cells was biased towards the defect/fatigue immune pattern, and the frequency of cells expressing NKp30 and member D of natural killer group 2 decreased, and the proportion of cells expressing T cell immunoglobulin and mucin domain increased. In addition, nKP30-positive NK cells have reduced expression of NCR3 immunostimulated splicing variants and increased expression of inhibitory variants, leading to NKP30-mediated loss of function in patients with advanced tumors.	Mantovani et al. (2019)
NK cells	Prognostic marker	Blocking the CD96−CD155 interaction restores NK cell immunity to tumor by reversing NK cell depletion or TGF-β1 reversing NK cell depletion, suggesting that CD96 may have a therapeutic role in HCC.	Sun et al. (2019a)
NK cells	The immune mechanism	When co-cultured with sorafenib treated M φ, cytotoxic NK cells were activated, resulting in tumor cell death. In addition, sorafenib was found to down-regulate the expression of major histocompatibility complex I in tumor cells, which may reduce tumor response to immune checkpoint therapy and promote NK cell response.	Hage et al. (2019)
NK cells	immunotherapy	Serum cholesterol accumulates in NK cells and activates their effect on HCC cells, increases the anti-tumor function of natural killer cells, and reduces the growth of liver tumors in mice.	Qin et al. (2020)
NK cells	The immune mechanism	CD48 protein was strongly expressed in HCC tissues but not in tumor liver monocytes. This monocyte induced NK cell dysfunction was significantly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blocking NKG2D and NKp30.	Wu et al. (2013)
NK cells	The immune mechanism	The cytotoxicity of NK cells in patients with HCC is reduced. MDSCs inhibit NK cell cytotoxicity and IFN-γ release. MDSCs inhibit NK cells depending on cell contact. MDSCs inhibit NK cells for a long time. MDSCs use NKp30 receptors to inhibit NK cell function.	Hoechst et al. (2009)
NK cells	The immune mechanism	Compared with donor and recipient PB, donor liver NK cells showed the strongest cytotoxicity to HCC HepG2 after IL-2 stimulation. This may explain why liver natural killer (NK) cells have higher cytotoxic activity against tumor cells than peripheral blood (PB) NK cells.	Ishiyama et al. (2006)
NK cells	The immune mechanism	SMICA derived from advanced HCC is responsible for NKG2D expression and NK cell function. NK cells stimulate DC maturation induced by human hepatoma cells and enhance the excitatory stimulation ability of DC. When NK cells were pretreated with serum containing SMicas, DC maturation and activation were completely eliminated.	Jinushi et al. (2005)
NK cells	immunotherapy	Leptin can significantly inhibit human HCC. This effect is mediated by inducing the proliferation and activation of natural killer cells and directly inhibiting tumor growth. The decreased NK expression of inhibitory CIS and the overexpression of anti-proliferative STAT2 and SOCS1 proteins in HCC lines may emphasize the anticancer effect of leptin.	Elinav et al. (2006)
NK cells	The immune mechanism	Smoking is associated with a decrease in the frequency of natural killer (NK) cells in the peripheral blood, which is characterized by a reduction in NK function through systemic immunology. The combination of smoking and lowering the frequency of NK cells further increases the likelihood of viral load and ALT≥80 U/L.	Wang et al. (2019b)
NK cells	The immune mechanism	NKT and CD4+T cells promote the elimination of senescent liver cells to prevent the occurrence of HCC, and this process requires CXCR6. CXCR6 inhibits the occurrence of HCC by promoting natural killer T and CD4+T cell-dependent senescence control.	Mossanen et al. (2019)
NK cells	immunotherapy	Using CAR transduced T cells and NK cells that recognize the surface marker CD147 (also known as Basigin), various malignant HCC cell lines were effectively killed in vitro, as well as HCC tumors in transplanted and patient-derived mouse models of transplanted tumors.	Tseng et al. (2020)
NK cells	The immune mechanism	The liver gene delivery of high IL-15 makes CD8+ T cells and NK cells proliferate in large quantities, resulting in the accumulation of CD8+ T cells in the body (over 40 days), especially in the liver. Hyper-IL-15 therapy has significant therapeutic effects on established liver metastases and even autologous HCC induced by DEN. These effects can be depleted by CD8+ T cells instead of NK cells.	Cheng et al. (2014)
NK cells	immunotherapy	The cytolytic activity of natural killer (NK) cells on ADAM9KD-HCC cells is higher than that on control cells, and the enhancement of this cytotoxicity depends on the MICA/B and NK group 2, D pathways. Sorafenib treatment resulted in a decrease in the expression of ADAM9 in HCC cells, an increase in the expression of membrane-bound MICA and a decrease in the level of soluble MICA. The addition of sorafenib enhanced the NK sensitivity of HCC cells by increasing the expression of membrane-bound MICA.	Kohga et al. (2010a)
NK cells	The immune mechanism	ADAM9 protease plays a key role in the shedding of MHC class I related chain A (MICA) that regulates the sensitivity of tumor cells to natural killer cells (NK). The expression of ADAM9 in CD133si-PLC/PRF/5 cells and CD133-Huh7 cells decreased, membrane-bound MICA increased, and soluble MICA production decreased. CD133si-PLC/PRF/5 cells and CD133-Huh7 cells are both sensitive to NK activity, which depends on the expression level of membrane-bound MICA, while HCC cells expressing CD133 are not.	Kohga et al. (2010b)
NK cells	The immune mechanism	CD8+ T cells and NKT cells promote NASH and HCC by interacting with hepatocytes, but not myeloid cells. NKT cells mainly cause steatosis by secreting light, and CD8+ and NKT cells synergistically induce liver damage. Hepatocyte LTβR and typical NF-κB signals promote the transformation of NASH to HCC, indicating that different molecular mechanisms determine the development of NASH and HCC.	Wolf et al. (2014)
NK cells	The immune mechanism	In-depth studies of the immune landscape show that regulatory T cells(T) and CD8 resident memory T cells(T) are enriched in hbv-related HCC, while Tim-3CD8 T cells and CD244 natural killer cells are in non-virus-related HCC In the enrichment.	Lim et al. (2019)
NK cells	The immune mechanism	Senescence monitoring requires the recruitment and maturation of CCR2 bone marrow cells, while CCR2 ablation induces HCC growth. In contrast, HCC cells inhibit the maturation of recruited myeloid precursors, which promote mouse HCC growth and deteriorate the prognosis and survival of human HCC patients by inhibiting NK cells.	Eggert et al. (2016)
NK cells	The immune mechanism	β-glucosylceramide alleviates immunologically incongruent disease by altering the plasticity of NKT lymphocytes and may be involved in the “fine-tuning” of the immune response.	Zigmond et al. (2007)
NK cells	The immune mechanism	Proliferating immune cells, mainly NK cells and T cells, were present in the patient’s long-lived tumor and consisted only of tumor cells lacking proliferation in the region. The density of NK cells and CD8+T cells was positively correlated with tumor cell apoptosis and negative proliferation.	Chew et al. (2010)
NK cells	immunotherapy	GS-9620 treatment is associated with a reversible increase in serum liver enzymes and thrombocytopenia, and induction of intrahepatic CD8+ T cells, NK cells, B cells, and interferon response transcriptional signaling.	Menne et al. (2015)
NK cells	The immune mechanism	Fibrosis is a way to enhance the occurrence of HCC. Changes in fibrosis also regulate the activity of inflammatory cells in the liver and reduce natural killing, which is generally helpful for tumors to monitor the activity of natural killer T cells. These pathways work in conjunction with inflammatory signals, including telomerase activation and the release of reactive oxygen species, ultimately leading to cancer.	Zhang and Friedman, (2012)
NK cells	immunotherapy	AdCMVmCD40L therapy can induce strong lymphocyte infiltration in tumor tissues and increase the apoptosis of malignant cells. The observed anti-tumor effect is mediated by CD8+ T cells and is related to increased serum levels of interleukin (IL)-12 and enhanced natural killer (NK) activity.	Schmitz et al. (2001)
NK cells	The immune mechanism	The activation of β-catenin in hepatocytes can change the liver microenvironment and lead to the specific targeting of iNKT cells. The activation of β-catenin in hepatocytes triggers the pro-inflammatory process related to the activation of NF- κ B. In the process of liver inflammation induced by β-catenin, iNKT cells showed anti-inflammatory properties. In HCC induced by β-catenin, iNKTs and LECT2 are the key cellular and molecular effectors to control tumor progression.	Anson et al. (2012)
NK cells	The immune mechanism	AdCMVIL-12 can activate natural killer cells (NK) and inhibit angiogenesis.	Barajas et al. (2001)
NK cells	The immune mechanism	Gene transfer of angiostatin inhibited tumor angiogenesis and enhanced NK cell infiltration, while B7H3 therapy activated CD8+ and NK cells and increased their infiltration into the tumor, and enhanced circulating IFN-γ levels.	Ma et al. (2007)