Non-alcoholic fatty liver disease (NAFLD) has become the fastest growing cause of hepatocellular carcinoma (HCC) in the United States, Europe, and South-East Asia. HCC related to non-alcoholic steatohepatitis (NASH), the inflammatory subtype of NAFLD, may soon become as prominent worldwide as viral HCC. While data from preclinical studies suggest that the efficacy of immunotherapy may be significantly reduced in NASH-related HCC (NASH-HCC) compared to viral HCC, conclusive clinical evidence is lacking.
The aim of this review was to assess the influence of NASH on the efficacy of current systemic and immune therapies to treat HCC. It underscores the therapeutic vulnerabilities associated with NASH-HCC, as well as the challenges and opportunities drawn from their exploitation.
NASH progression has been shown to be associated with innate and adaptive immune dysfunction, which overlaps with immune checkpoint inhibitors’ (ICIs) mechanism of action. ICI-based therapies, including the combination of atezolizumab and bevacizumab, are the new standard of care in the systemic first-line treatment for HCC.
Preliminary data has suggested that compared to patients with viral HCC, ICIs were less effective in patients with nonviral HCC. This reduction in efficacy could be due to pathophysiological factors associated with NAFLD and NASH, which include altered immune-microenvironments and gut dysbiosis.
Despite these findings, biomarkers to predict outcomes in HCC patients undergoing immunotherapy remain to be discovered. To address this unmet medical need and determine the therapeutic vulnerabilities specific to NASH-HCC, biomarker development should be systematically integrated alongside drug development programmes.