Immune checkpoint blockade has changed the treatment options for advanced hepatocellular carcinoma, but only a minority of patients achieve lasting responses, largely due to tumor heterogeneity and an immunosuppressive tumor microenvironment. Predictive biomarkers like programmed death‑ligand 1 expression and tumor mutational burden have shown value in other cancers but remain limited in hepatocellular carcinoma.
Researchers from The Chinese University of Hong Kong published a review in Cancer Biology & Medicine (May 2026) that explores how the gut microbiome affects immunotherapy responses in hepatocellular carcinoma. The study brings together recent evidence showing that gut bacteria, their metabolites, and intratumoral microbes actively shape the liver's immune environment. By detailing mechanisms underlying microbial modulation of anti-tumor immunity, the authors outline possible uses for probiotics, dietary interventions, and fecal microbiota transplantation to improve efficacy and safety of immunotherapy for liver cancer.
The review highlights several discoveries. Under healthy conditions, the gut‑liver axis maintains immune balance through beneficial bacteria such as Lactobacillus reuteri and Akkermansia muciniphila; these are associated with protective microbial metabolites including short-chain fatty acids like acetate and butyrate. In hepatocellular carcinoma, dysbiosis occurs: harmful species such as Klebsiella pneumoniae and Catenibacterium mitsuokai expand, producing toxic metabolites like deoxycholic acid and quinolinic acid that drive chronic inflammation and promote tumor growth. One finding shows that Catenibacterium mitsuokai binds to liver cells and secretes quinolinic acid, which activates pathways fueling cancer progression. Intratumoral bacteria such as Enterococcus faecalis and Streptococcus anginosus have been detected within tumors; they may contribute to an immunosuppressive environment dominated by myeloid-derived suppressor cells with reduced cytotoxic T-cell infiltration.
The review also identifies specific microbial signatures linked to resistance against immunotherapy—such as enrichment of Phocaeicola vulgatus—which impairs CD8+ T-cell cytotoxicity by disrupting tryptophan metabolism. The authors said, "We've moved from seeing the gut microbiome as just a biomarker to understanding it as an active driver of immunotherapy success or failure in liver cancer." They continued, "Certain bacteria essentially hijack the gut‑liver axis, producing metabolites that either warm up the tumor environment for immune attack or turn it cold and resistant to treatment. The most exciting part is that this is modifiable. By restoring a healthy microbial ecosystem—whether through specific probiotics, diet, or fecal transplants—we may be able to turn non‑responders into responders. That's a powerful new angle for personalized cancer therapy."
Potential clinical implications include using gut microbial profiles as non-invasive biomarkers to predict which patients will benefit from immune checkpoint blockade therapy; interventions such as Bifidobacterium supplementation or dietary fiber could enhance response rates; ongoing trials are testing strategies combining fecal microbiota transplantation with standard therapies in patients who failed prior treatments.
