The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma

Simple Summary The liver can be considered an immune organ, given its role as a hub for gut-derived antigens and liver-resident immune cells and the tolerance status of its environment. However, chronic inflammation represents a disruption to this balance and, pathogenetically, represents the beginning of a multistep process leading to cancer. The present study aimed to describe the key points of liver cancer pathogenesis, which may help in understanding the limits and perspectives of investigations concerning immunotherapy. In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.