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an effective strategy to improve tumor infiltrating lymphocyte infiltration and function. Moreover, CAR-T
cell therapy in combination with PD-1 blockade overcomes PD-L1-mediated cancer immunosuppression
and leads to enhanced therapeutic efficacy [147] . The combination of CTLA-4 blockade with ACT also
generates greater therapeutic efficacy [148] . Besides systemic delivery of checkpoint blockade, the knockout of
immune checkpoint in CAR-T cells by gene-editing technologies improves anti-tumor efficacy of CAR-T
cells in various cancer models by enhancing effector function and survival of T-cells [149] . It is understood that
the immunosuppressive trait of the HCC microenvironment requires combinational therapeutic modalities
for effective outcome [150] . These findings support combination immunotherapy with immune checkpoint
blockade and ACT for cancers, which is expected to result in greater anticancer immune response than with
either intervention alone.

CONCLUSION
Following significant therapeutic progress made on the basis of basic research, immunological studies offer
a new era of clinical application. Immunotherapy brings a new hope to depressed patients with chronic
infection, autoimmune disease, or cancers. More importantly, cytotoxic immune cell-based immunotherapy
has markedly improved survival in patients with advanced cancers. The high mortality of patients with
advanced HCC owing to resistance to chemotherapy highlights the importance and value of immunotherapy
in HCC treatment, although the clinical efficiency has not been as promising as expected. The development
+
of novel ICIs, cytokines, tumor-specific antigens, gene-modified/CAR NK cells, and TCR/CAR CD8 T cells
is expected to improve the curative effect. Furthermore, the flexible combination of immunotherapy and
other therapies might offer the much required breakthrough in clinical efficacy of HCC treatment.

DECLARATIONS
Authors’ contributions
Contributed to conception and design of the study and manuscript writing: Li J, Tao L, Wang X
Final approval of manuscripts: Li J, Tao L, Wang X

Availability of data and materials
Not applicable.

Financial support and sponsorship
This manuscript publication is funded by the Natural Science Foundation of China (#31872741), Anhui
Provincial Natural Science Foundation (grant numbers: 1708085QH183 and 1808085QC83), and Young
Top Talent Program of Anhui Medical University, and Research Improvement Program of Anhui Medical
University.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable

Copyright
© The Author(s) 2020.