Dual regulatory role of natural killer T cells during development of hepatocellular carcinoma

Natural killer T (NKT) cells play a complex role in hepatocellular carcinoma (HCC) progression. Using a diethylnitrosamine (DEN)-induced HCC mouse model, we observed a significant reduction in NKT cells within malignant liver tissue due to apoptosis, with the remaining cells exhibiting impaired cytokine production and cytotoxic potential. CD1d-deficient mice, which lack NKT cells, showed delayed tumor initiation and fewer tumors, yet the tumors that did form were larger and exhibited enhanced proliferation and immunosuppression. Notably, adoptive transfer of healthy NKT cells after tumor establishment reduced tumor burden, suggesting a protective role in later disease stages. These findings indicate that NKT cells contribute to early tumor development but may help control tumor progression in later stages. Their functional impairment in HCC underscores the need for strategies to restore their anti-tumor activity. Understanding the dual role of NKT cells in liver carcinogenesis may pave the way for novel immunotherapeutic approaches to improve HCC treatment and patient outcomes. In HCC, NKT cells promote early tumor development but restrain later growth. Adoptive transfer of healthy NKT cells after tumor establishment reduces tumor burden, highlighting their potential as immunotherapeutic targets in HCC.