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Page 2 of 15 Feng et al. Hepatoma Res 2021;7:3 I http://dx.doi.org/10.20517/2394-5079.2020.107

INTRODUCTION
Hepatocellular carcinoma (HCC) accounts for 75%-85% of all primary liver cancers. Due to the rapid
progression of HCC, the lack of effective treatment programs, and poor prognosis makes it the fourth
[1]
leading cause of cancer-related deaths . Due to regional differences in medical diagnosis and treatment,
more than half of the new cases and deaths of HCC each year occur in the Asia-pacific region. Patients
[2]
with early HCC in Europe and United States can be diagnosed and effectively treated in time . More than
70% of HCC patients do not benefit from medical therapy. The vast majority of HCC patients present
with an advanced stage at diagnosis, and the most effective surgical programs are often challenging
to implement. In the past ten years, dozens of promising chemotherapeutics have failed the phase III
[3]
trial, with only sorafenib demonstrating a low objective response rate and a slight increase in survival .
Research on targeted drugs for cell proliferation, metastasis and angiogenesis are encouraging, such as
[4]
regorafenib and lenvatinib, although the overall survival rate remains dissatisfactory . The ineffectiveness
of chemotherapeutics and targeted drugs may be due to drug resistance and heterogeneity of HCC. HCC
is usually accompanied by severe chronic liver damage and cirrhosis. Hence, anti-HCC drugs require a
good balance of therapeutic response and drug toxicity and this often limits the application of highly active
[5,6]
compounds with high toxicity . Therefore, restoration of the liver microenvironment caused by chronic
injury should be incorporated in the holistic management of HCC. In recent years, immunotherapy has
been used in the treatment of various solid tumors. This was observed through the checkpoint inhibition
of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) and cell toxic T lymphocyte-
associated protein 4 (CTLA-4) while improving the tumor immune microenvironment which seems to be
particularly relevant for the treatment of HCC. However, the unique liver immune system and resident
immune tolerance state make it different from other organs. Besides, continuous matrix remodeling
of the malignant hepatocyte transformation caused by chronic inflammation and scars has created an
immunosuppressive microenvironment that promotes the development of HCC, posing a challenge for
[7]
HCC immunotherapy .
THE IMMUNE MICROENVIRONMENT OF THE LIVER AND HCC
The liver has a unique immune regulation and balance mechanism. On one hand, the portal vein system
is directly exposed to gastrointestinal pathogens and requires an effective immune response. On the other
hand, it needs to deal with a large number of harmless blood antigens and maintain the immune tolerance
[8]
[9]
of the liver . In most cases, the liver is in a physiological immune tolerance state . Most non-parenchymal
cells, such as live sinusoidal endothelial cells (LSEC), Kupffer cells (KCs) and hepatic dendritic cells
(HDC), gather in the liver sinusoids. It constitutes the physiological basis of the liver’s immunosuppressive
microenvironment [10,11] . LSEC has the dual functions of immune surveillance and immune tolerance. It acts
[12]
as an antigen-presenting cell (APC) to present pathogens or tumor antigens . At the same time, it inhibits
the excessive responses of DC and T lymphocytes to bacterial antigens from the portal system [13-15] . KCs
maintain immune tolerance by engulfing pathogenic microorganisms derived from the intestine, secreting
inhibitory factors (such as IL-10 and prostaglandins) and activating the proliferation of regulatory T cells
(Tregs) [16-19] . Besides, HDC is also a component of the liver immune tolerance by reducing the expression
[20]
of MHC II and co-stimulatory molecules . In summary, this immune-tolerant physiological environment
creates a huge obstacle to the host’s anti-tumor immunity.

The pathogenesis of HCC is characterized by destruction of the sinusoidal structure by a viral infection and
inflammatory injury, impairment of immune surveillance and immune tolerance functions leading to liver
cirrhosis and liver cancer [6,10] . The high-risk factors of HCC (hepatitis virus, alcohol, aflatoxin, etc.) drive
hepatocyte DNA damage, endoplasmic reticulum stress and necrosis, which in turn leads to the formation
[21]
of regenerative nodules, proliferative nodules and ultimately HCC . HCC has abundant immune cell
infiltration, which is the immune response of the host trying to clear the tumor. Unfortunately, this immune