Hepatocelullar Carcinoma
About Lesson

Hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer, with approximately 90% of cases linked to advanced fibrosis caused by viral hepatitis, excessive alcohol intake, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH- now known as  MASLD). The liver’s unique immune microenvironment plays a pivotal role in HCC pathogenesis, balancing both pro-tumorigenic and anti-tumorigenic effects. Like many tumours, it has been proved that inactivartion of tumour suppresors such as p53 along wit abnormal activation of oncogenes (K-ras, etc.,) remains the main mechanism rather than mutations. A very common mutation is Telomerase Reactivation (TERT mutations- 30%–60% of all HCC) particularly those in the gene promoter region, lead to increased TERT expression. This upregulates telomerase activity, enabling cancer cells to bypass normal cellular aging and apoptosis.

In chronic liver inflammation, multiple cell types—including macrophages, stellate cells, endothelial cells, and various lymphocyte subtypes—interact with hepatocytes. Mouse models have shown that immune signals like IL-6, TNF, and lymphotoxin-α can accelerate hepatocarcinogenesis and influence tumor aggressiveness. However, immune responses can also limit liver cancer progression through immune surveillance and the elimination of pre-malignant or malignant hepatocytes. Importantly, the liver harbors the largest number of immune cells in the body and maintains a tolerant immune state to endure the constant flow of inflammatory signals from the gut. This immune tolerance can, paradoxically, promote tumor progression.

Key Mechanisms of Immune-Mediated HCC Promotion

  1. Cytokines and Growth Factors: Immune cells secrete cytokines and growth factors that enhance tumor cell proliferation and inhibit apoptosis.
  2. Lymphocyte Suppression: Certain immune responses suppress the anti-tumor functions of neighboring lymphocytes.

The NF-κB and JAK–STAT pathways are central inflammatory signaling pathways in HCC development, as confirmed by human transcriptome analyses. In contrast, the presence of immune infiltrates is associated with better prognosis due to enhanced anti-tumor immunity.

In general, it is as many other cancers, a stepwise process (low grade dysplastic nodule → high grade dysplastic nodule → early hepatocellular carcinoma → progressed hepatocellular carcinoma) accompanied by accumulation of molecular alterations

The adaptive immune system’s role in HCC is gaining attention in the context of immuno-oncology therapies. Notably, studies suggest that VEGF secreted by malignant hepatocytes creates an immune-tolerant, pro-tumorigenic microenvironment. Blocking the VEGF cascade—through combinations of immune checkpoint inhibitors (ICIs) and VEGF-targeted therapies—has shown enhanced survival benefits compared to single-agent treatments.

In summary, this complex interplay between immune cells, inflammatory signaling pathways, and the liver’s immune state is critical for developing effective immunotherapies to treat HCC.