Microbiome–Immune Interactions as Determinants of Checkpoint Inhibitor Efficacy in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains a major global health challenge and one of the leading causes of cancer-related mortality, with advanced disease continuing to be associated with limited therapeutic options and substantial heterogeneity in response to systemic treatment. Recent evidence has established the gut microbiota, through the gut–liver axis, as a critical determinant of immunotherapy efficacy, while also influencing antitumor immunity and liver carcinogenesis. Microbial dysbiosis may promote chronic inflammation, intestinal barrier disruption, bacterial translocation, and immune dysfunction, thereby contributing to hepatocarcinogenesis. Moreover, gut microbial composition and microbial-derived metabolites, including bile acids, short-chain fatty acids (SCFAs), and inosine, have been associated with modulation of antitumor immune responses and differential outcomes to immune checkpoint inhibitors (ICIs). Emerging clinical evidence in HCC has identified distinct gut microbial signatures associated with response to nivolumab, pembrolizumab, and atezolizumab-based regimens, including enrichment of Akkermansia muciniphila and SCFA-producing taxa such as Ruminococcaceae, Roseburia, and Prevotella in responders. However, these findings remain inconsistent across studies, with no reproducible microbial signature identified because of small cohort sizes, heterogeneous patient populations, geographic variation, cirrhosis-related confounding factors, and methodological differences in microbiome analysis. This review summarizes the current understanding of microbiome–immune interactions in HCC, examines mechanistic pathways linking the microbiota to immunotherapy response, critically evaluates available clinical evidence, and discusses current limitations and future therapeutic strategies, including fecal microbiota transplantation, probiotics, dietary modulation, and engineered bacterial platforms. Collectively, microbiome-based approaches may contribute to the development of personalized immunotherapeutic strategies in HCC, although larger standardized prospective studies are required before microbiome-derived biomarkers can be implemented in routine clinical practice.