A review led by Professor Jun Yu at the Chinese University of Hong Kong, China, was published in Volume 2 of the journal Immunity & Inflammation on October 8, 2026. The article systematically examines how gut microbiota and their metabolites reshape the hepatic immune microenvironment through the gut–liver axis, influence immune checkpoint inhibitor efficacy, and explore emerging combination strategies, including fecal microbiota transplantation, probiotics, engineered bacteria, and metabolite-based interventions.
The liver continuously receives microbial products and metabolic signals from the gut via the portal vein, making the gut microbiota a direct modulator of hepatic inflammation and tumor immunity. When microbial homeostasis is disrupted, intestinal barrier integrity is compromised, leading to increased permeability. Pathogen-associated molecular patterns then enter the liver and activate innate immune cells, sustaining chronic inflammation. Microbial molecules such as lipopolysaccharide, bile acids, short-chain fatty acids, and tryptophan derivatives regulate oxidative stress and DNA damage, influencing cellular senescence, fibrosis, and hepatocarcinogenesis. Thus, the gut–liver axis is not a one-way metabolic conduit but a regulatory network linking barrier function, metabolic homeostasis, immune cell differentiation, and anti-tumor responses.
Why do patients receiving the same immunotherapy have different outcomes? The efficacy of immune checkpoint inhibitors depends not only on tumor target expression but also on whether the hepatic microenvironment supports effective immune responses. The review points out that gut microbial composition and metabolites influence the balance between intrahepatic effector and suppressive immune cells, determining whether treatment leads to response or resistance. CD8 + T cells, NKT cells, dendritic cells, and innate lymphoid cells participate in anti-tumor responses, while regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells form an immunosuppressive barrier. Predicting treatment efficacy may therefore not rely solely on tumor tissue analysis. Fecal microbiota structure, blood or bile metabolite profiles, and local hepatic immune status could all be incorporated into a more comprehensive assessment system.
Moving from “microbiota association” to “mechanism-driven” understanding is critical. The key is not simply which bacteria increase or decrease but how they reshape immune cell function. Short-chain fatty acids, bile acid derivatives, and tryptophan metabolites affect antigen presentation, T cell activation, myeloid cell polarization, and the inflammatory tone within the liver. Some metabolites enhance cytotoxic immune responses, while others exacerbate immunosuppression and treatment resistance. Microbial metabolites are not inherently “beneficial” or “harmful”; their effects depend on liver disease etiology, tumor stage, immune context, and local concentration. What truly matters is the dynamic interaction among the microbiota, metabolites, and host immune system.
Reversing resistance requires more than simply supplementing a “good bacterium.” The review discusses four major directions of gut microbiota intervention. First, probiotics and prebiotics improve intestinal barrier function, reduce endotoxin load, and modulate metabolite production. Second, fecal microbiota transplantation aims to restore microbial functions associated with favorable immune responses through ecological “reset.” Third, engineered bacteria and synthetic consortia can deliver immunomodulatory molecules locally within tumors or precisely regulate metabolic pathways. Fourth, metabolite supplementation and metabolic pathway intervention use short-chain fatty acids, bile acid derivatives, and tryptophan metabolites as immunotherapy-sensitizing tools. The common goal is not merely to increase beneficial bacteria but to rebuild a gut–liver axis ecosystem that supports antigen presentation, effector T cell activation, and tumor immune clearance.
Translating these concepts into clinical practice still requires overcoming three major hurdles. First, most existing clinical cohorts remain at the association level, and causality has not been fully established. Second, diet, geography, cirrhosis severity, antibiotic exposure, sequencing platforms, and liver cancer etiology can all affect the reproducibility of microbiota findings. Third, probiotic strain selection, donor screening for fecal microbiota transplantation, and construction of engineered bacteria still require rigorous standardization, and long-term safety and efficacy endpoints remain to be defined. The next key step is not only to conduct more microbiome studies but also to establish research frameworks that integrate multi-omics, mechanistic validation, and prospective clinical trials, facilitating the translation of “correlative discoveries” into actionable precision therapeutic regimens.
“ The next breakthrough in liver cancer immunotherapy may not only come from discovering new targets on tumor surfaces but may also begin with a group of microbes in the gut, a metabolic remodeling event, or a reactivated gut–liver immune pathway, ” the authors concluded. When gut microbiota, microbial metabolites, and the hepatic immune microenvironment are integrated into a single therapeutic framework, immune checkpoint inhibitors may no longer “fight alone.” “ Future precision immunotherapy for liver cancer may need to simultaneously answer three questions, ” the authors highlighted, “ What is the patient's tumor immune status? What support can the gut microbiota provide? And how can controllable microbiota interventions awaken otherwise silent anti-tumor immune responses? ”
Reference
Title of original paper: Gut microbial and metabolic modulation in enhancing immunotherapy in hepatocellular carcinoma
Journal: Immunity & Inflammation
DOI: https://doi.org/10.1007/s44466-026-00056-y
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Professor Jun Yu from Chinese University of Hong Kong, China
Dr. Jun Yu is Professor of Internal Medicine and Therapeutics at the Chinese University of Hong Kong, Assistant Dean of the Faculty of Medicine, Director of the Institute of Digestive Disease, and Director of the State Key Laboratory of Digestive Disease. She is a Foreign Member of the Academia Europaea and a Fellow and Co-President of the Hong Kong Academy of Sciences. She has received over 50 major awards, including two National Natural Science Awards (Second Class), the National Science and Technology Progress Award (Second Class), the National Science and Technology Progress Award for Innovation Team, the Ho Leung Ho Lee Foundation Prize for Scientific and Technological Progress, the Guanghua Engineering Science and Technology Award, the Wu Jieping-Paul Janssen Medical and Pharmaceutical Award, four First Prizes from the Ministry of Education, and the American Gastroenterological Association Research Mentor Award (the first Asian recipient).
Funding information
This work was supported by the Noncommunicable Chronic Diseases National Science and Technology Major Project (2023ZD0500200); Research Grants Council-General Research Fund (14117123, 14119524, and 24119525), and National Natural Science Foundation of China (82272619).
Immunity & Inflammation
Systematic review
Not applicable
Gut microbial and metabolic modulation in enhancing immunotherapy in hepatocellular carcinoma
8-Oct-2026
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.