Gut microbial and metabolic modulation in enhancing immunotherapy in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. HCC immunosuppressive tumor microenvironment limits therapeutic efficacy, while immune checkpoint inhibitors (ICI) have produced only modest response rates in many patients. Emerging evidence highlights the lack of ICI response in patients with metabolic dysfunction-associated steatohepatitis-related HCC. This review examines the role of the gut–liver axis in shaping HCC progression across different etiologies and immunotherapy responsiveness, with emphasis on how microbial dysbiosis and microbiota-derived metabolites contribute to immune reprogramming. Furthermore, we evaluate the potential of baseline microbial composition and functional metabolite profiles as predictive biomarkers for immunotherapy response. Therapeutic strategies under investigation include fecal microbiota transplantation, probiotics, engineered bacterial strains, and metabolite-based adjuvants. Despite promising preclinical findings, major translational barriers remain, including interpatient heterogeneity, limited mechanistic validation, and insufficient clinical standardization. Overall, microbiome-based modulation represents a promising adjunct to immunotherapy in HCC and may support the development of more precise and durable clinical treatment strategies.