Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

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  Figure 1. The potential contribution of TNF-α and adiponectin to the pathogenesis of NAFLD-associated HCC. In NASH, TNF-α is produced by dysfunctional adipocytes, lipid-stressed hepatocytes, and various immune cell populations that reside in the liver (KCs) or infiltrate the liver, including myeloid-derived monocytes, neutrophils, NKT cells, CXCR6+ PD1+ TNF+ CD8+ T cells, and CD4+ Th1 cells. TNF-α activates NF-κB, which, although under basal condition may prevent hepatocarcinogenesis, when overactivated, as in the setting of NASH, may contribute to hepatocarcinogenesis. In addition, TNF-α promotes hepatocyte death, which is mediated by the DISC II. Also, TNF-α activates specific tumor-associated pathways (i.e., the JNK pathway) in affected hepatocytes and promotes the proliferation and differentiation of HPCs, all of which contribute to hepatocarcinogenesis. In NASH-associated HCC microenvironment, TNF-α promotes the accumulation of several immune-suppressive cells, such as neutrophils, TAMs, MDSCs, Tregs, and B cells, which impair the function of anti-tumor CD8+ T cells. In addition, TNF-α induces the expression of PD-L1 by tumor cells, which interacts with PD-1 expressed on anti-tumor…

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  Figure 2. Combinational therapy for NAFLD-associated HCC. Emerging preclinical evidence suggests that ICIs, which are currently considered the standard of care for patients with advanced HCC, independent of the underlying etiology, may be less effective particularly in patients with NAFLD-associated HCC. It has been hypothesized that the dysmetabolic and inflammatory microenvironment in NAFLD and NAFLD-associated HCC, which potentially impacts the functionality of the immune system, may set the basis for repurposing metabolic-targeted therapies (therapies that target impaired metabolic pathways in NAFLD, such as IR, hepatic steatosis, adiponectin levels) or anti-inflammatory therapies (therapies against key inflammatory mediators, such as TNF-α) in combination with systemic immunotherapy against NAFLD-associated HCC. Abbreviations: CTL-4, cytotoxic T-lymphocyte-associated protein-4; HCC, hepatocellular carcinoma; ICIs, immune checkpoint inhibitors; IR, insulin resistance; GLP-1RAs, glucagon-like peptide-1 receptor agonists; NAFLD, nonalcoholic fatty liver disease; NF-κΒ, nuclear factor-kappa B; PPAR, peroxisome proliferator-activated receptors; PD-1, programmed death-1; PDL-1, programmed…