Pamungkas KMN, Lesmana Dewi PIS, Alamsyah AZ, Dewi NLPY, Dewi NNGK, Mariadi IK, Sindhughosa DA. Microbiome dysbiosis and immune checkpoint inhibitors: Dual targets in Hepatocellular carcinoma management. World J Hepatol 2025; 17(7): 106810 [DOI: 10.4254/wjh.v17.i7.106810]
Corresponding Author of This Article
Dwijo Anargha Sindhughosa, MD, Researcher, Divison of Gastroenterology and Hepatology, Department of Internal Medicine, Udayana University, Faculty of Medicine, Jl. Diponegoro, Denpasar 80113, Bali, Indonesia. dwijo_anargha@unud.ac.id
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Jul 27, 2025; 17(7): 106810 Published online Jul 27, 2025. doi: 10.4254/wjh.v17.i7.106810
Microbiome dysbiosis and immune checkpoint inhibitors: Dual targets in Hepatocellular carcinoma management
Kadek Mercu Narapati Pamungkas, Putu Itta Sandi Lesmana Dewi, Ajib Zaim Alamsyah, Ni Luh Putu Yunia Dewi, Ni Nyoman Gita Kharisma Dewi, I Ketut Mariadi, Dwijo Anargha Sindhughosa
Kadek Mercu Narapati Pamungkas, Putu Itta Sandi Lesmana Dewi, Ajib Zaim Alamsyah, Ni Luh Putu Yunia Dewi, Ni Nyoman Gita Kharisma Dewi, I Ketut Mariadi, Dwijo Anargha Sindhughosa, Centre Research for Alimentary and Hepatobiliary System, Denpasar 80113, Bali, Indonesia
I Ketut Mariadi, Divison of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine Udayana University/Ngoerah Hospital, Denpasar 80113, Bali, Indonesia
Dwijo Anargha Sindhughosa, Divison of Gastroenterology and Hepatology, Department of Internal Medicine, Udayana University, Faculty of Medicine, Denpasar 80113, Bali, Indonesia
Co-corresponding authors: I Ketut Mariadi and Dwijo Anargha Sindhughosa.
Author contributions: Sindhughosa DA designed the manuscript outline and coordinated the writing process; Mariadi IK contributed to drafting and critically revising the manuscript for important intellectual content; Pamungkas KMN was involved in the study’s conception, in-depth review, image production, and manuscript writing; Dewi PISL contributed to manuscript writing and peer-reviewed specific content; Alamsyah AZ participated in manuscript writing and image production; Dewi NLPY contributed to writing and proofreading the manuscript; Dewi NNGK was involved in manuscript writing. All authors approved the final version of the article.
Conflict-of-interest statement: All authors declare that they have no competing interests.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dwijo Anargha Sindhughosa, MD, Researcher, Divison of Gastroenterology and Hepatology, Department of Internal Medicine, Udayana University, Faculty of Medicine, Jl. Diponegoro, Denpasar 80113, Bali, Indonesia. dwijo_anargha@unud.ac.id
Received: March 10, 2025 Revised: April 19, 2025 Accepted: June 13, 2025 Published online: July 27, 2025 Processing time: 140 Days and 3.4 Hours
Abstract
Hepatocellular carcinoma (HCC), a primary malignancy of the liver and leading cause of cancer-related mortality worldwide, poses substantial therapeutic challenges, particularly in advanced and unresectable stages. Immune checkpoint inhibitors (ICIs) have emerged as critical therapeutic agents, targeting immune checkpoint pathways to restore antitumor immune responses. Combinations such as atezolizumab (anti-programmed cell death ligand 1 with bevacizumab (anti-vascular endothelial growth factor), as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1 (e.g., ipilimumab and nivolumab), have demonstrated improved clinical outcome in selected patients. However, the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance. Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs. Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness. Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation, prebiotics, probiotics, and fecal microbiota transplantation to enhance ICIs responsiveness. This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC, with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.
Core Tip: Combination of immune checkpoint inhibitor (ICI) therapy has improved efficacy and survival in patients with unresectable hepatocellular carcinoma (HCC). However, a substantial proportion still fail to respond due to resistance driven by the tumor microenvironment. Emerging strategies targeting gut microbiota offer promising avenues to overcome this barrier. Certain microbial taxa have been associated with enhanced T-cell infiltration and improved ICI responses. Additionally, microbial metabolites like butyrate and desaminotyrosine exert immunomodulatory effects that may restore sensitivity to ICIs. Dual-target approaches combining ICIs and microbiota modulation hold potential to improve progression-free and overall survival in HCC.
