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Page 4 of 15 Feng et al. Hepatoma Res 2021;7:3 I http://dx.doi.org/10.20517/2394-5079.2020.107

oncolytic virus therapy can also selectively replicated in tumors, killing cancer cells while stimulating
antigen presentation and adaptive anti-tumor immune responses.

IMMUNE CHECKPOINT INHIBITORS
Tumor cells express a variety of immunosuppressive ligands on their surface, which bind to the indicated
inhibitory receptors of activated T cells involved in the anti-tumor response. This process in turn reduces
[33]
the intensity of the anti-tumor immune response, thereby evading immune surveillance . Drugs that
block these immunosuppressive targets to eliminate tumor immune escape are called immune checkpoint
inhibitors (ICI). PD-1 is a member of the CD28 superfamily and is expressed on the surface of T cells and
B cells. Its activation will lead to the phosphorylation of ITSM (Immunoreceptor tyrosine-based switch
motif) in the cytoplasm of the cell, inhibiting energy metabolism in T cells, thereby hindering cell cloning
proliferation and secretion of cytokines. In order to avoid the killing of T cells, tumor cells highly express
PD-L1 and release the PD-L1 into the peripheral blood, which causes the exhaustion of T cells and the
[34]
loss of tumor antigen presentation ability of myeloid immune cells . Therefore, targeted inhibition of the
interaction of PD-1 and PD-L1 is of great significance for the treatment of HCC.

Nivolumab, as the first PD-1 targeted drug to be used in clinical practice, was initially used in the
treatment of melanoma, and its objective response rate and one-year survival rate were 40.0% and 72.9%,
[35]
respectively . Subsequently, Nivolumab was tried to treat advanced HCC. Among 144 HCC patients, 20%
showed a good response to nivolumab, and 3 of them achieved complete remission (CR), highlighting the
potential of Nivolumab to treat advanced HCC . Another anti-PD-1 targeted drug Pembrolizumab has
[36]
also shown effectiveness in the treatment of advanced HCC, with an objective response rate and a one-
[37]
year survival rate of 17% and 54% . In fact, a single ICI is not satisfactory for the treatment of advanced
HCC. The current ICI therapy is mostly performed in a variety of combinations (for example, anti-
PD-L1 antibody plus anti-CTLA-4 antibody), which is more effective than a single agent. In the absence
of targetable lymphocytes in the tumor microenvironment, inhibition of PD-1/PD-L1 cannot stimulate
cancer immunity, and inhibition of the CTLA-4 can cause CD8 + T cells to proliferate in the lymph nodes
and infiltrate the tumor tissue, thereby enhancing the efficacy of anti-tumor. In fact, combination therapy
of molecularly targeted drugs and immune checkpoint inhibitors has received considerable attention. For
example, immunosuppressive cytokines that cause the immunosuppressive liver environment of patients
with liver cancer, such as interleukin (IL)-10, transforming growth factor (TGF)-β and vascular endothelial
growth factor (VEGF) molecular targeted drugs [38,39] . Table 1 shows the ongoing use of ICI in combination
with various interventions (such as kinase inhibitors, cytokine or receptor inhibitors, and embolotherapy).

ONCOLYTIC VIRUS THERAPY
The oncolytic virus can specifically host in cancer cells, replicate and destroy the cell structure and hence
was not initially classified as immunotherapy. Subsequent studies confirmed that oncolytic viruses could
induce anti-cancer immune responses and immunogenic cancer cell death, making them a form of
[47]
immunotherapy . Compared with traditional therapies, oncolytic virus therapy is safer, has the selective
specificity of host cancer cells, and continuously self-replicates to lyse cancer cells . In the tumor
[48]
microenvironment, pathogen-associated molecular patterns (PAMP) of oncolytic viruses can be recognized
by pattern recognition receptors (PRR) of immune cells, such as through TLR or MDA5 activation of
macrophages or dendritic cells [49,50] . As a secondary effect, oncolytic viruses enhance the recognition and
presentation of tumor antigens, and activate the infiltration of cytotoxic T cells into tumors . Therefore,
[51]
oncolytic virus therapy is a very interesting method to overcome HCC immunosuppression. Currently,
oncolytic virus therapies used for HCC include dsDNA or ssRNA viruses, such as measles vaccine virus
(MeV), herpes simplex virus (HSV), adenovirus (Adenovirus) and vaccinia virus (VV), etc., which are
[52]
used to engineer infection vectors . For example, inserting the overexpression sequence of granulocyte-