Insights in the Immune Molecular Mechanisms of the Trilogy of Liver Cancer

ABSTRACT: Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) being its predominant form, accounting for 90% of cases. HCC is closely linked to chronic inflammation and fibrosis driven by factors such as hepatitis B and C, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). In the liver, persistent regenerative responses trigger activation of hepatic stellate cells (HSCs), collagen deposition, and fibrosis, which collectively pave the way for carcinogenesis. For patients diagnosed in the early stages of liver cancer, curative options such as surgical resection or liver transplantation may be viable. However, the majority of cases are diagnosed at advanced stages, rendering surgical intervention unsuitable. Systemic treatments for advanced liver cancer often show limited efficacy, highlighting the importance of understanding liver cancer’s development processes to enhance early diagnosis and therapeutic strategies. This review delves into the molecular mechanisms underpinning the progression of liver cancer, tracing the pathological continuum from hepatitis to cirrhosis and ultimately to liver cancer. It explores the immune responses activated during this transition, particularly focusing on inflammatory responses and their central roles. Furthermore, it highlights the significance of inflammatory cytokines and HSCs in liver fibrosis, which creates a microenvironment conducive to cancer development. The review also examines immune regulation and cell signaling in the tumor microenvironment, offering insights into the transformation from hepatitis to liver cancer and paving the way for improved treatment strategies.