Non-alcoholic fatty liver disease (NAFLD) has gained attention in the last few years due to its increasing prevalence worldwide becoming a global epidemic. The increasing incidence of NAFLD and the concurrent increase in the number of hepatocellular carcinoma (HCC) cases at a global level is a matter of concern. HCC has several risk factors, of which NAFLD and its associated metabolic disturbances-type 2 diabetes mellitus, obesity, and dyslipidemia-are of great interest due to their accelerating rise in incidence worldwide. There is a high amount of data derived from basic and clinical studies that reveal the molecular pathways that drive NAFLD-associated HCC. Based on these findings, new prevention, surveillance, and treatment strategies are emerging. However, current data on treatment modalities in NAFLD-associated HCC are still scarce, though the results from non-NAFLD HCC studies are promising and could provide a basis for a future research agenda to address NAFLD/NASH patients. Clinicians should carefully assess all the clinical and radiological parameters and establish a prognosis based on the Barcelona Clinic Liver Cancer classification and discuss in a multidisciplinary team the treatment strategy. The specific factors associated with NAFLD-associated HCC which can have a negative impact on survival even in patients with early HCC, such as cardiovascular disease, type 2 diabetes, and obesity, should be taken into consideration. This review aims to discuss the latest recommendations regarding the diagnosis and treatment of NAFLD-associated HCC and the remaining challenges.

Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated literature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25% of the global population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC. Therefore, low-calorie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC. Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoembolization, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Given the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.

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.

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.

In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying aetiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation are characterised by several unique features: in contrast to virally driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and are more frequently diagnosed at an advanced stage. While locoregional treatments are probably equally effective regardless of HCC aetiology, the picture is less clear for systemic therapy. Tyrosine kinase inhibitors are probably equally effective, while there have been initial signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. Current international clinical practice guidelines for HCC do not consider aetiology, as there are insufficient data to draw specific conclusions or to recommend aetiology-specific modifications to the current management of patients with HCC. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC aetiology - and NAFLD/NASH in particular - influence the safety and efficacy of a given treatment.