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(including patient-derived and mo-DCs) confer the next-generation DC vaccines superior functionalities
for presenting MHC-I/II antigen and eliciting CTL responses . Pulsing DCs with CD44 and epithelial cell
[43]
adhesion molecule (EpCAM) peptides can activate cancer stem-like cells (CSCs) peptide-specific immune
responses leading to better clinical outcomes when combined with standard chemotherapy for advanced
carcinomas . Cytoplasmic transduction peptide (CTP), a novel antigen delivery tool, can transduce tumor
[44]
antigen such as the forkhead box protein M1 (FoxM1) into the cytosol of DCs .
[45]

Vaccination approaches
Many studies have focused on pre-conditioning the DC-based vaccine sites and have already reported some
interesting discoveries. The lymph node homing and immune function of tumor antigen-specific DCs can
be significantly improved by pre-conditioning the vaccine site with a potent recall antigen, such as tetanus/
diphtheria (Td) toxoid. A significant increase in both PFS and overall survival (OS) in Td-treated patients
compared with DC-treated patients has been approved for clinical trials . Furthermore, RNA-lipoplexes
[46]
(RNA-LPX) encoding endogenous self-antigens or mutant neo-antigens or viral can enable precise and
effective targeting of DCs and perform effectively in vivo, as well as induce strong effector and memory T cell
responses. This could result in a universally applicable vaccine type for DC based cancer immunotherapy .
[47]
Exosomes derived from AFP-expressing DCs (DEX ), another type of vaccine for cancer immunotherapy
AFP
elicits strong antigen-specific immune responses and restructures the microenvironment in tumor . DCs
[48]
can also be loaded via RNA transfection or recombinant viral transduction .
[49]
[50]
Immune checkpoints-specific antibodies
The interactions between an APC and a T cell through the TCR-antigen/MHC complex simultaneously
trigger both co-stimulatory and co-inhibitory signals. The balance between these signals determines the
overall activation and function of T cells. Several co-inhibitory molecules (PD-1, CTLA-4, BTLA-4, LAG-3,
TIM-3 and CD160) expressed on the surface of T cells are the targets of antibodies [51-55] . Checkpoint blocking
antibodies have been approved by the FDA since 2014 for patients with lung cancer, melanoma, and other
tumors. For HCC, CTLA-4 and PD-1 antibodies have been intensely investigated and are both advancing to
the clinical trial stage.

CTLA-4
Blocking CTLA-4 induces a strong antitumor immune response , and research on CTLA-4 is ongoing [57,58] .
[56]
CTLA-4 blockers were mainly ipilimumab and tremelimumab. In 2011, FDA approved ipilimumab for
the treatment of melanoma. However, for the CTLA-4 molecular targeted therapy, only tremelimumab is
currently undergoing clinical trials related to liver cancer. In a phase II clinical trial of tremelimumab ,
[59]
median OS was 8.2 months and median TTP was 6.48 months among all 21 patients enrolled. Among the
17 patients continuously treated with tremelimumab, no complete remission (CR) was observed, while 3
patients (17.6%) had confirmed partial remission (PR) that was maintained up to 3.6, 9.2 and 15.8 months,
respectively. Overall, a good safety profile was recorded and no treatment-related death occurred. The
feasibility and safety of tremelimumab combined with ablation (chemoablation or radiofrequency ablation)
in patients with advanced HCC was assessed in another clinical trial . Among the 19 patients evaluated,
[60]
5 patients (26%) achieved confirmed PR. The median OS was 12.3 months and median TTP was 7.4 months
with a median potential follow-up of 18.8 months for the total study population (n = 28). Tremelimumab
was well tolerated across the different dose cohorts and no dose-limiting toxicities (DLT) was encountered.
Recently, ipilimumab, another drug combined with the fully humanized anti-CTLA-4 IgG1 antibody, has
been investigated in several clinical trials. These results have not been published.

PD-1/PD-L1
PD-1 is expressed on T cells binding with its ligand (PD-L1, PD-L2) [61,62] . PD-L1 is expressed on APC and
[63]
negatively regulates downstream signals of T cell receptor stimulation to reduce T cell activation and cytokine