Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?

Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.