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NK cell therapy
NK cells have potent anticancer capacity. HLA class I molecule-independent activation endows NK cells
with more potential for extensive applications. HLA class I molecules block the NK cell killing though
interaction with KIRs or CD94/NKG2A/B on NK cells [106] . Meanwhile, stress-induced ligands on cancer
cells can activate NK cells by interacting with activation receptors on them [107] . However, NK cell function is
impaired and hardly restored in advanced cancers. Hence, adoptive transfer of NK cells is a valuable option
for cancer therapy. However, adoptive transfer of autologous lymphokine-activated NK cells with IL-2 into
patients with metastatic cancer led to a poor clinical outcome [108] , which might be attributed to high levels of
HLA class I molecules on cancer cells and the exhausted function of patients’ NK cells. To overcome these
defects, allogeneic NK cells - especially allogeneic haploidentical NK cells - are harnessed to treat various
malignancies [109] . Encouraging clinical efficacy has been observed in trials of acute myeloid leukemia [110] .
Moreover, cryoablation combined with allogeneic NK cell therapy markedly improved the progression-free
survival of patients with advanced HCC [111] . Besides autologous and allogeneic NK cells, NK-92 cells, an
NK cell line, is also used in clinical trials of cancer therapy, with encouraging results observed in patients
with advanced lung cancer [112] . To enhance the targetability of NK cells, Chimeric antigen receptor (CAR)-
NK cells have also been developed and pre-clinically evaluated. NK-92 cells with CD19-CAR display potent
+
ability to kill CD19 leukemia cell lines and lymphoblasts from patients with leukemia [113] . NK-92 cells with
+
GPC3-CAR show significant in vitro cytotoxicity to GPC3 HCC cells and potent anticancer activity in
HCC xenografts [114] . Accumulating evidence indicates that NK cell therapy is a potential approach for HCC
treatment with technical improvements in the activation and expansion of NK cells.

Cytokine-induced killer cell adjuvant therapy
Cytokine-induced killer (CIK) cells generated from blood mononuclear cells cultured with IFN-γ, anti-
CD3, and IL-2 show potent anticancer activity [115] . Jia et al. [116] reported that CIK cells improved overall
survival in HCC. CIK cell adjuvant therapy also reduces the recurrence in HCC patients undergoing curative
treatment [117] . Lee et al. [118] found that the efficacy of CIK cells in patients with HCC lasted over 5 years.
+
Chang et al. [119] reported that the high number of PD-1 tumor infiltrating lymphocytes could predict the
response and clinical benefits of CIK cell adjuvant immunotherapy in HCC patients. Pan et al. [120] reported
that CIK cell cytotoxicity is a predictive biomarker for adjuvant CIK cell immunotherapy of HCC patients
after surgery. Collectively, increasing evidence suggests that CIK cell-based adjuvant immunotherapy shows
modest efficacy in early-stage HCC. Although Wang et al. [121] showed that intraperitoneal perfusion of CIK
cells with local hyperthermia was safe for patients with advanced HCC, more clinical data on the efficacy of
CIK cell therapy in advanced HCC is currently lacking. Further detailed studies on the characteristics of CIK
cells and their recognition and effector function are required to improve the clinical outcomes of CIK cell
adjuvant immunotherapy in HCC.

CAR-redirected T cell therapy
CAR-T cells have shown tremendous clinical efficacy in the therapy of hematological malignancies [122] .
Moreover, CAR-T cell therapy is expected to convert cold tumors into hot tumors, which represents a
promising immunotherapeutic option for HCC treatment. Glypican-3 (GPC3) is a membrane heparan
sulfate and is highly expressed in HCC tissues [123,124] . Unfortunately, the GPC3-targeted antibody - GC33 -
was unsuccessful in bringing about clinical benefit to patients with HCC [125] . However, the anti-GPC3/anti-
CD3 bispecific antibody - ERY974 - could activate T cells and convert the microenvironment of a cold tumor
to that of a hot one [126] . Therefore, GPC3 is a promising target of CAR-T cells in HCC. Indeed, GPC3-CAR-T
+
cells could eliminate GPC3 HCC cells and tumors in a patient-derived xenograft model [127] . GPC3-CAR-T
therapies have been registered for clinical trials. To overcome T-cell exhaustion induced by checkpoints, an
enhanced version of CAR-T cells is being currently designed. For instance, PD-1 is disrupted via CRISPR/
Cas9 to enhance the activity of GPC3-CAR T cells against HCC [128] . A soluble PD-1-CH3 fusion protein
is expressed to increase anticancer activities of GPC3-CAR-T cells [129] . Co-expressing GPC3-CAR and co-