• NONALCOHOLIC STEATOHEPATITIS
• HEPATOCELLULAR CARCINOMA
• IMMUNOTHERAPY

Liver cancer remains a global health burden, and hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases. HCC can have viral causes, for example, chronic hepatitis B virus or hepatitis C virus infections, and non-viral causes such as non-alcoholic steatohepatitis (NASH) or alcohol-related liver cirrhosis. Particularly HCC related to NASH increased tremendously over the past decade and is expected to rise further. NASH, the advanced form of non-alcoholic fatty liver diseases (NAFLD), is characterised by chronic liver inflammation as a consequence of lipid accumulation and metabolic injury in the liver. This inflammatory hepatic environment in NASH is critical for driving HCC, so that HCC can even develop in non-cirrhotic NASH livers.1 The introduction of immune checkpoint inhibition (ICI) as the new first-line systemic therapy for HCC has raised substantial concerns whether ‘T-cell activation’ with ICI as part of the tumour defence would be similarly efficacious in NASH-related versus viral induced HCC.2 In fact, a recent meta-analysis had indicated reduced efficacy of ICI-based regimen in NASH-HCC, possibly related to the unique immune environment in NASH-HCC livers which is characterised by a combined immunosuppressive and pro-inflammatory milieu.3 In these livers, not only exhausted tumour-specific PD-1⁺CD8 T cells exist but also tissue-damaging, autoaggressive CXCR6⁺PD-1⁺ CD8 T cells, which explains why PD-1 therapy might also have tumour-promoting effects in NASH-induced HCC.4 5 Clearly, optimised immunotherapy in NASH-induced HCC is required to specifically reinvigorate tumour-specific CD8 T cells to promote anti-tumour immunity.

In this issue of Gut, Leslie et al highlight tumour-associated neutrophils (TANs) as a potential mechanistic contributor as well as a potential therapeutic target in NASH-HCC.5 They demonstrated that in preclinical NASH-HCC mouse models, which respond poorly to …