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stimulatory molecule ICOSL-41BB promotes CAR-T cell proliferation and tumor rejection [130] . Besides
GPC3, MUC-1, EpCAM, AFP, and CEA might be potential targets of CAR T cells for HCC treatment,
which have been registered for clinical trials on the applicability of CAR-T therapy as a treatment strategy
for HCC [131] . Moreover, these classical tumor-associated antigens and ligands for receptors expressed on T
cells also act as the targets for HCC recognition. For instance, NKG2D-based CAR-T cells could potently
+
eliminate NKG2DL HCC cells [132] . A CD147-targeted inducible CAR-T cell system has been developed
for HCC treatment [133] . Although clinical trials of CAR-T therapy against HCC have not been completed,
CAR-T therapy might provide effective therapeutic modalities for HCC treatment. Nonetheless, to date,
the therapeutic efficacy of CAR-T cells remains limited owing to the lack of cancer-specific targets, weak
expansion, poor infiltration, and induced exhaustion of CAR-T cells. Hence, smarter optimization strategies
and more clinical trials are required for the confirmation and improvement of clinical outcomes of CAR-T
cells in HCC treatment.

T cell receptor-genetically engineered T cell therapy
The success of T cell receptor-genetically engineered T (TCR-T) cells in melanoma treatment has encouraged
the use of TCR-T cells in HCC treatment. Autologous T cells forced to express an HBV-specific TCR
+
recognized HBsAg HCC cells and decreased HBsAg levels in a patient who underwent liver transplant [134] .
T cells genetically engineered with HCV NS3:1406-1415-reactive TCR recognized the naturally processed
+
antigen and led to suppression of HCV HCC in vivo [135] . T cells genetically engineered with AFP-specific
+
TCR specifically recognized and killed AFP HepG2 cells, both in vitro and in vivo [136] . Although there
remain many challenges such as off-target cross-reactivity and low TCR affinity that need to be overcome
before successful translation into clinical practice [137,138] , increasing findings suggest that TCR-T therapy
might be an attractive alternative immunotherapeutic modality for HCC treatment.

DC-vaccines adjuvant immunotherapy
Briefly, DCs are professional antigen-presenting cells with the capacity to prime antigen-specific T-cell
immunity. DC vaccines are recognized as promising agents for activating T cells to eliminate cancer cells;
their role and functions have been evaluated in some malignancies in clinical trials, including HCC. A phase
II study using intravenous vaccination with DCs pulsed with HepG2 lysate was found to be safe and showed
evidence of anticancer efficacy in some patients with advanced HCC [139] . Another phase I/II study reported
that vaccination with DCs pulsed with AFP peptides induced strong T-cell immunity against AFP but no
clinical responses in HCC patients [140] . Other phase I/IIa studies also reported that subcutaneous vaccination
with DC pulsed with multiple antigens such as AFP, glypican-3 (GPC-3), and melanoma-associated antigen
1 (MAGE-1) enhanced anticancer immunity and prolonged time-to-recurrence and recurrence-free survival
in HCC patients [141-143] . Interestingly, Lu et al. [144] showed that exosomes derived from AFP-expressing DCs
elicited potent anticancer immune responses and cancer regression in HCC mice, thus providing a novel
option for vaccine-based immunotherapy of HCC. Pang et al. [145] reported that DCs fused with cancer stem
cells could efficiently stimulate T lymphocytes to generate specific CD8 T cells against cancer stem cells.
Collectively, several studies indicate that DC vaccine-based adjuvant therapy enhances anticancer immunity
and improves the survival of patients with HCC. Nonetheless, further improvements such as specific
immunogenic neoantigens for HCC, safe and feasible DC source, potent adjuvant, and access to vaccination
are required for future success of DC-based HCC immunotherapy.

Combination therapy of immune checkpoint blockade and adoptive cell transfer
The existence of cancer immunosuppressive microenvironment limits the effector function of adoptive
immune cells. Therefore, it is reasonable to improve the cancer immunosuppressive microenvironment to
enhance the curative efficacy of adoptive immune cells on HCC. Kodumudi et al. [146] reported that adoptive
transfer of tumor infiltrating lymphocytes from tumors with anti-PD-L1 antibody treatment led to a
significant delay in tumor growth, suggesting that pretreatment with immune checkpoint blockade could be