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World J Gastrointest Oncol. Sep 15, 2022; 14(9): 1622-1636
Published online Sep 15, 2022. doi: 10.4251/wjgo.v14.i9.1622
Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows
Federico Costante, Carlo Airola, Francesco Santopaolo, Antonio Gasbarrini, Maurizio Pompili, Francesca Romana Ponziani
Federico Costante, Carlo Airola, Francesco Santopaolo, Antonio Gasbarrini, Maurizio Pompili, Francesca Romana Ponziani, Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
Antonio Gasbarrini, Maurizio Pompili, Francesca Romana Ponziani, Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
Author contributions: Costante F and Airola C revised literature; Costante F, Airola C, Santopaolo F and Ponziani FR wrote the paper; Pompili M, Gasbarrini A, Santopaolo F and Ponziani FR supervised and revised the paper.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
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: Francesca Romana Ponziani, MD, PhD, Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, Roma 00168, Italy. francesca.ponziani@gmail.com
Received: March 18, 2022
Peer-review started: March 18, 2022
First decision: April 17, 2022
Revised: May 5, 2022
Accepted: July 5, 2022
Article in press: July 5, 2022
Published online: September 15, 2022
Abstract

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.

Keywords: Hepatocellular carcinoma, Immunotherapy, Liver cancer, Nonalcoholic fatty liver disease, Metabolic dysfunction-associated fatty liver disease, Obesity

Core tip: Complex interactions involving the immune system, angiogenesis and inflammation are associated with the pathogenesis of hepatocellular carcinoma (HCC). Recent reviews suggested lower efficacy of immunotherapy in patients with nonviral HCC. This calls into question the need to stratify patients to maximize the effectiveness of immunotherapeutic agents. In this study, we provided the latest report on the tumor microenvironment structure and its implications in response to immunotherapy in nonalcoholic fatty liver disease-related HCC and also discussed the efficacy of first-line systemic treatment in this patient population.