The Role and Mechanistic Effects of Gut Microbiota Metabolites in Immunotherapy for Hepatocellular Carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced hepatocellular carcinoma (HCC), but low response rates and drug resistance remain major clinical challenges. Recent data underscore the gut-liver axis as a major determinant of therapeutic outcomes, particularly amid an epidemiological transition towards chronic liver diseases. In this review, we summarize the effects of gut microbiota-derived metabolites on the hepatic tumor immune microenvironment (TIME) and the efficacy of ICIs. Beneficial metabolites such as short-chain fatty acids and primary bile acids promote anti-tumor immunity by enhancing the infiltration and cytotoxicity of CD8+ T cells, NK cells, and NKT cells. On the contrary, immunosuppressive metabolites such as secondary bile acids and kynurenine promote exhausted TIME, induce M2 polarization of macrophages, and immune evasion. In addition, structural differences between lipopolysaccharides and tryptophan-derived indoles directly modulate toll-like receptor activation and signaling pathways, including NF-κB, PI3K/Akt, and JAK/STAT3. Elucidation of these complex metabolic networks provides critical insights into mechanisms of ICI responsiveness. Collectively, current evidence supports gut-derived metabolites as promising candidates for predictive biomarkers and therapeutic modulation; however, prospective validation, mechanistic confirmation in humans, and standardized microbiome profiling remain necessary before routine clinical implementation.