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Page 2 of 18 Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04

With the development of surgical techniques, HCC may be cured by surgical resection or liver
transplantation in the early stage. In addition, some early malignancies may be cured by prompt local
treatment such as radiofrequency ablation (RFA) or percutaneous ethanol injection treatment. Unfortunately,
due to the concealed and rapid progress of HCC, most patients have lost the chances of best treatment
by the initial visit. Only a fraction of patients with HCC have the opportunity for these treatments. As
for the patients who are not suitable for surgery or RFA, stereotactic body radiation therapy, portal vein
[2]
embolization and other liver-directed therapies have become the standard treatment means . In recent
years, with the great scientific and technological advances, systemic therapy has been adopted by most
hepatobiliary surgeons under conditions of appropriate liver function and good physical condition.

In the past several decades, many genetic alterations in HCC have been confirmed by previous mechanism
studies, such as aberrant activation of oncogenes and the inactivation of anti-oncogenes. Apart from gene
mutations, changes in epigenetics such as chromatin modification, DNA methylation, gene recombination,
histone modification, RNA interference and copy number variation have been proven to play a critical part
[3]
in the development of primary liver cancer .

The tumor microenvironment plays a vital role in tumorigenesis and cancer development and metastasis,
which can be divided into an immune microenvironment characterized by immune cells and non-
immune microenvironment characterized by fibroblasts. The majority of immune cells of the tumor
microenvironment include T lymphocytes, B lymphocytes, macrophages, natural killer (NK) cells and
[4]
antigen-presenting cells (APCs) . In the microenvironment of the liver tumor, the composition and
proportion of immune cells play vital roles in the progress of tumorigenesis [Figure 1]. Compared to other
organs, the liver is richer in immune cells, including natural killer T cells (NKT cells), Kupffer cells and
[5]
NK cells . Moreover, inactivation of immunosuppressive cytokines (such as IL-4, -5, -8, -10, etc.) and
immune activating cytokines (such as TNF, IL-1, etc.) tends to produce an immunosuppressive environment.
Constant exposure to antigen at higher concentrations from the gastrointestinal tract induces the liver to
[6]
develop intrinsic immune tolerance and immune evasion to ward off autoimmune injury . Since intrinsic
immune tolerance and immune escape are often connected with HCC tumorigenesis, a growing number of
studies point to immunotherapies (such as vaccines, adoptive cell therapies, immune checkpoint blockade,
cytokines, etc.) targeting the microenvironment as a new strategy against hepatic cancer to bring new hope
to patients with HCC. In this article, we reviewed the important role of the microenvironment in HCC
tumorigenesis and the recent advances of immunotherapy in HCC.

ROLE OF IMMUNE CELLS IN LIVER TUMOR MICROENVIRONMENT
The tumor microenvironment contains a series of immune cells including NK cells, dendritic cells (DCs),
macrophages, regulatory T cells (Tregs), neutrophils, T cells and eosinophils [Figure 1]. The function and
number of immune cells both matter in the liver immune microenvironment, and related changes are
frequently observed in the development of HCC. Multiple immune cells will promote tumor occurrence and
development by activating or inhibiting various complex signaling pathways.

Tumor-associated macrophages
Previous works have established that there are monocyte-derived macrophages divided into M1 and
[7]
M2 phenotypes . Tumor-associated macrophages (TAMs) are a significant component of the liver
microenvironment, being very important to tumor development and thus resulting in the poor outcome of
HCC patients. Preclinical studies have shown that TAMs suppress the immune system and promote tumor
[8,9]
progression through the expression of chemokines and cytokines . It has been reported that CCL17,
CCL18 and CCL22 can block the activation of cytotoxic T cells by attracting Tregs to tumor sites [10-12] . TAMs
interact with bone myeloid-derived suppressor cells (MDSCs) to lower major histocompatibility complex
[13]
II (MHCII), IL-6 and IL-12 levels and increase IL-10 production . IL-10 produced by TAMs increases the