Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide. Despite significant improvements in the treatment landscape for advanced HCC in recent years through combination therapies centered on immune checkpoint inhibitors (ICIs), only approximately 20%-30% of patients achieve durable clinical responses. Primary and acquired resistance remain critical bottlenecks limiting broader efficacy. Traditionally, investigations into resistance mechanisms have predominantly focused on the tumor microenvironment (TME), emphasizing the formation of an immune-"cold" niche, the compensatory upregulation of alternative immune checkpoints [e.g., lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT)], and dynamic metabolic reprogramming. However, this tumor-centric perspective fails to fully account for the observed inter-patient heterogeneity in treatment efficacy, suggesting the critical involvement of systemic regulatory factors. Grounded in the unique anatomical and physiological connectivity of the "gut-microbiota-liver axis", the gut microbiota, as a critical extrahepatic regulatory system, is increasingly recognized for its role in influencing hepatic immune homeostasis and anti-tumor responses. This provides a novel breakthrough for systemically understanding and overcoming immunotherapy resistance in HCC. The gut microbiota systemically regulates immune surveillance in the liver and the immune status of the tumor microenvironment through various mechanisms, including metabolites (such as short-chain fatty acids, secondary bile acids, and tryptophan metabolites), the activation of pattern recognition receptors, and antigen cross-reactivity. Clinical evidence indicates significant differences in gut microbial community structure between responders and non-responders, while antibiotic use may impair the efficacy of ICIs by disrupting microbial homeostasis. Consequently, microbiota-targeted interventions have emerged as promising strategies to reverse immunosuppression and re-sensitize tumors to immunotherapy. Modalities such as fecal microbiota transplantation (FMT), next-generation probiotics/synbiotics, metabolite-based therapies, and engineered bacteria have progressed from concept to early-stage clinical practice, demonstrating initial safety and feasibility. This article systematically reviews the mechanisms and clinical evidence regarding the role of the gut microbiota in immunotherapy resistance for HCC, and discusses its translational prospects as a personalized combination therapeutic strategy, aiming to provide new insights for overcoming bottlenecks in HCC immunotherapy.
KW - Hepatocellular carcinoma KW - immunotherapy resistance KW - gut microbiota KW - immune checkpoint inhibitors KW - tumor microenvironment DO - 10.20517/2394-5079.2026.03 UR - https://dx.doi.org/10.20517/2394-5079.2026.03