Table 2.

Effects of chronic HBV infection and NAFLD on HCC development.

	Mechanistic role/pathways	Effect on HCC development	References
CHRONIC HBV INFECTION	HBsAg→impaired activity of NK cells	enhanced progression to HCC	(169–173)
	inflammatory stimuli and viral proteins→M2-like tumor macrophages	promotion of HCC progression	(174–176)
	HbeAg→upregulation of PD-L1→polarization to M2 protumor subtype
	HBV-mediated macrophage release of matrix metalloproteinase 9 (MMP9) and IL-23 → blockade of IFNa to IFNAR1	tumor progression and angiogenesis	(177–182)
	HbeAg→MDSCs expansion→dampen T cell function via IDO pathway
	HbsAg→activation of ERK/IL-6/STAT3 signaling axis→differentiation of MDSCs
	CCRK→virus-host signaling
	↓CXCR5+CD4+ Tfh→↓ICOS, IL-10, IL-21→↓Plasmablasts	insufficient anti-tumoral immunity, enhance evasion of tumor cells	(183–187)
	CD8+ T cell, Treg exhaustion, ↑CTLA-4, PD-1 and TIM-3, ↓antibody production
	↑NLR, Foxp3+ Treg cells	tumor immune escape and metastasis	(188–190)
	↑TGF-β activity→ ↓microRNA-34a→ ↑CCL22→Treg cells
	↑PD-1 in peripheral blood CD4+ and CD8+ T cells		(191–195)
	↑PD-1, FcRL4 and FcRL5 in HBsAg-specific B cells→ defective antibody production
	HBsAg suppresses CREB→ ↓TLR9 on B cells→ ↓proliferation of B cells and pro-inflammatory cytokine release
	↑immunosuppressive type of B cells→ ↓cytotoxic activity of T cells
NAFLD	↑neutrophils→ ↑matrix metalloproteinase-9	angiogenesis	(196)
	↑PD-L1+ monocytes → ↓tumor specific T cell immunity	insufficient anti-tumoral immunity, poor survival	(197)
	Tregs and MDSCs→immunosuppression of CD8+ T cells and NK cells	tumor immune escape	(161, 198, 199)
	NK dysregulation by IL-15, NK→less cytotoxic ILC1-like phenotype→↓kill cancer cells
	CCRK-AR signaling→ ↑mTORC1/4E-BP1/S6K/SREBP1 →MDSCs→metabolic reprogramming and immunosuppression	enhance progression to HCC, impaired anti-tumor immune surveillance	(167)
	lipid accumulation → MDSCs→ ↑ROS production, loss of intrahepatic CD4+ T cells		(200, 201)
	Platelet glycoprotein Ibα-mediated aggregation and activation of platelets - KCs	hepatic inflammation and progression to HCC	(202)
	↑linoleic acid→ ↑ROS production in CD4+ T cells→cell apoptosis	impaired anti-tumor immune surveillance	(203, 204)
	exhausted hepatic PD1+CD8+ T cell, ↑CXCR6
	Th17 cells→ induction of VEGF/E2/PGE2, activation of ongogenic IL-6/Stat3 signalling	tumor growth and angiogenesis	(205–207)
	IgA+ plasma cells →PD-L1 mediated suppression of CD8+ T cells, ↓IL-10	inhibition of anti-tumor immunity	(208–210)
	B regulatory cells, producing IL-10/CD40/CD154 signaling pathway