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It is generally accepted that tumor development and progression are closely linked to the failure of immune
surveillance, which includes elimination of tumor cells at the initial stage or immune defense to prevent im-
[68]
mune escape . In general, activated CD8+ T cells are essential in anti-cancer immunity, while regulatory T
[69]
cells (Tregs) mediate significant immune dysfunction against cancer . The main reason for the decline of
anti-cancer immunity is T cell dysfunction or exhaustion. Several factors responsible for this phenomenon
have been proposed, including abnormal increases in check point inhibitors, such as programmed cell death
protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4), lymphocyte activation gene 3 protein (LAG3),
[70]
and killer cell lectin-like receptor G1 (KLRG1) . Moreover, tumor-infiltrating lymphocytes (TILs) sur-
rounding cancer play an important role in host immunosurveillance associated with tumor biology. TILs
present in HCC are composed of intratumoral CD8+ T cells and peritumoral CD4+ T cells independent of
[71]
[72]
histogenetic origin but their roles in tumor killing are not clearly understood. More recently, Zheng et al.
carried out deep scRNA-seq on 5063 single T cells isolated from peripheral blood, tumor, and surround-
ing non-tumoral tissue from 6 HCC patients. Analyzing the transcriptional profiles of these individual cells
coupled with assembled T cell receptor (TCR) sequences, 11 functional T cell subsets were identified based
on their molecular and functional properties. Specific subsets, such as exhausted CD8+ T cells and Tregs, are
preferentially enriched and potentially clonally expanded in HCC. FOXP3, CTLA4, TNFRSF18, TNFRSF4
and CCR8 were highly expressed in tumor-infiltrating Tregs, while MYO7A, WARS, andCXCL13 LAYN,
PHLDA1, and SNAP47 were identified in tumor-infiltrating exhausted CD8+ T cells. In particular, high
expression of PHLDA1 and SNAP47 was significantly associated with poor prognosis in HCC patients. In
addition, it was demonstrated that LYAN was highly expressed in both tumor Tregs and exhausted CD8+ T
cells from tumor tissue of HCC and shown that LYAN is up-regulated on activated CD8+ T cells and Tregs,
[72]
repressing the CD8+ T cell function in vitro . These data are crucial for understanding hepatocarcinogen-
esis and developing targeted immunotherapies in HCC.

CONCLUSION
The pathogenesis of HCC is very complicated and depends on the specific etiologic factors involved. HCC
pathogenesis is a multistep process that involves diverse molecular and cellular signaling pathways. For this
reason, patients with HCC should be managed with multiple therapeutic modalities by multidisciplinary
teams rather than a single treatment approach to achieve better clinical outcomes. The major risk factors for
HCC include hepatitis B and C virus infection, alcohol, NAFLD, chemical toxins and hereditary disorders.
During hepatocarcinogenesis, numerous factors, such as oxidative stress, inflammation, hormone systems,
hypoxia and immunity, are dysregulated, leading to the development of HCC. Nonetheless, the precise mo-
lecular mechanisms defining the development of HCC have not been entirely elucidated. Emerging scRNA-
seq technology is a powerful tool for defining sub-populations of cells within a heterogeneous bulk of tumor
tissue and has been a breakthrough that has the potential to unveil the molecular mechanisms of HCC. In
addition, single-cell genome analysis can be applied to monitor circulating tumor cells and cell-free DNA to
evaluate tumor recurrence. Moreover, analysis of the transcriptome heterogeneity and characterization of
the heterogeneous molecular signatures in HCC will lead to development of novel therapeutic target agents
and ultimately help tailor individual cancer therapy.

DECLARATIONS
Authors’ contributions
The author contributed solely to the paper.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This research was supported by grants of Global High-tech Biomedicine Technology Development Program