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World J Gastroenterol. Jul 28, 2022; 28(28): 3595-3607
Published online Jul 28, 2022. doi: 10.3748/wjg.v28.i28.3595
Non-alcoholic fatty liver disease-related hepatocellular carcinoma: Is there a role for immunotherapy?
Ângelo Z Mattos, Jose D Debes, Arndt Vogel, Marco Arrese, Xavier Revelo, Tales Henrique S Pase, Muriel Manica, Angelo A Mattos
Ângelo Z Mattos, Angelo A Mattos, Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
Ângelo Z Mattos, Angelo A Mattos, Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90050-170, Brazil
Jose D Debes, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States
Jose D Debes, Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam 999025, Netherlands
Arndt Vogel, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
Marco Arrese, Department of Gastroenterology, School of Medicine and Center for Aging and Regeneration, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
Xavier Revelo, Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, United States
Tales Henrique S Pase, Muriel Manica, Internal Medicine Unit, Irmandade Santa Casa de Miser-icórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
Author contributions: All authors contributed to this paper with conception of the manuscript, literature review and analysis, drafting and critical revision of the manuscript, and approval of the final version of the paper.
Supported by European-Latin American ESCALON Consortium, Funded By The EU Horizon 2020 Program, No. 825510; Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program to JDD; University of Minnesota Academic Investment Research Program–AIRP Grant to JDD; Fondo Nacional de Ciencia y Tecnología de Chilex to MA, No. FONDECYT-1191145; Agencia Nacional de Investigación y Desarrollo to MA, No. ANID-ACE 210009.
Conflict-of-interest statement: Dr. Mattos reports grants from EU Horizon 2020 program, grants from Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program, grants from Fondo Nacional de Ciencia y Tecnología de Chile and Comisión Nacional de Investigación, Ciencia y Tecnología , grants from University of Minnesota Academic Investment Research Program–AIRP grant, grants from Agencia Nacional de Investigación y Desarrollo (ANID ACE 210009), during the conduct of the study.
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: Ângelo Z Mattos, MD, MSc, PhD, Professor, Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, 245 Sarmento Leite St., Porto Alegre 90050-170, Brazil. angmattos@hotmail.com
Received: February 14, 2022
Peer-review started: February 14, 2022
First decision: April 5, 2022
Revised: June 26, 2022
Accepted: June 26, 2022
Article in press: June 26, 2022
Published online: July 28, 2022
Abstract

Hepatocellular carcinoma (HCC) is among the most common cancers and it is a major cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD) affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC. The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood. However, metabolic, fibrogenic, oncogenic, inflammatory and immunological pathways seem to be involved. First-line therapy of advanced HCC has recently undergone major changes, since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib. Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy. However, initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease, which seems to be particularly important in NAFLD-related HCC, as these tumors might not benefit from it. This article will review the mechanisms of NAFLD-related hepatocarcinogenesis, with an emphasis on its immune aspects, the efficacy of traditional systemic therapy for advanced NAFLD-related HCC, and the most recent data on the role of immunotherapy for this specific group of patients, showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.

Keywords: Non-alcoholic fatty liver disease, Hepatocellular carcinoma, Hepatocarcinogenesis, Immun-ology, Immunotherapy, Tyrosine kinase inhibitors

Core Tip: Non-alcoholic fatty liver disease (NAFLD) is an important cause of hepatocellular carcinoma (HCC). While the treatment of advanced HCC has recently undergone a revolution led by immunotherapy, concerns have been raised that NAFLD-related HCC might not respond well to these new therapies. This review will approach the pathophysiology of NAFLD-related liver cancer, the evidence on traditional systemic treatments and the most recent data on immunotherapy for this particular group of patients, showing that the management of this condition should be individualized.