Invariant Natural Killer T cells control positively and negatively the development of hepatocellular carcinoma

The liver routinely encounters antigens from the gut, triggering pro-inflammatory responses. Unresolved inflammation can lead to liver damage, steatosis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCC is influenced by various immune cells, including invariant natural killer T (iNKT) cells, which exhibit both innate and adaptive immunity traits. Here, we examined iNKT cell dynamics in a diethyl-nitrosamine (DEN)-induced HCC mouse model. We observed a significant reduction in iNKT cell numbers in HCC livers due to apoptosis and impaired cytokine production. CD1d-deficient mice, which lack iNKT cells, displayed delayed tumor initiation and lower tumor and foci number. However, these tumors were larger in size and characterized by enhanced proliferation and immunosuppression. Interestingly, adoptive transfer of healthy iNKT cells post-tumor establishment reduced tumor burden, highlighting their potential therapeutic role. Our findings suggest that iNKT cells contribute to early HCC development, while in later stages they help to control tumor growth, thus underscoring their complex role in liver carcinogenesis. Further understanding of iNKT cell functions may inform novel immunotherapeutic strategies for HCC management.