Gut-Liver Microbiome and Tumor Microenvironment in Metabolic Dysfunction-Associated Steatotic Liver Disease

Hepatocellular carcinoma (HCC), the dominant form of primary liver cancer associated with cirrhosis, has been increasing in prevalence in the US and globally. Metabolic dysfunction-associated steatotic liver disease (MASLD), which is linked to the obesity pandemic and growing prevalence of metabolic disorders, has played a major role in this worrisome trend. Notably, up to 50% of MASLD-associated HCC develop in the noncirrhotic liver, suggesting different mechanisms of carcinogenesis as compared to HCC associated with other chronic liver diseases and potentially resulting in delays in diagnosis. Unfortunately, HCC has an unfavorable prognosis once advanced, and systemic therapies used in the management of advanced HCC have limited efficacy and considerable toxicity. More insight into HCC pathophysiology is therefore urgently needed to improve both preventive and therapeutic strategies. The gut-liver axis, and specifically the gut microbiome, appears to play a major role in the development and progression of HCC. MASLD is associated with dysbiosis, and HCC is a serious outcome of a dysfunctional relationship between the liver and the gut microbiome. Microbial-derived metabolites and cell wall components, which reach the liver via the portal and biliary circulation, may have direct oncogenic effects or activate pathways of cell proliferation, inflammation, and immunosuppression, thus altering the liver tumor microenvironment. In addition, the recent discovery of the intratumoral microbiome offers novel opportunities to learn about the host-microbiome relationship, hepatocarcinogenesis, and tumor surveillance. Further insight into the dysfunctional gut-liver axis and immuno-oncology-microbiome axis in MASLD promises to advance strategies for HCC prevention and treatment.