N6-methyladenosine (m6A) Writer WTAP Potentiates Hepatocellular Carcinoma Immune Evasion and Aerobic Glycolysis

Abstract

Hepatocellular carcinoma (HCC) is one of most prevalent malignant tumors with poor prognosis and a high mortality rate. Recent research indicates that N⁶-methyladenosine (m⁶A) and tumor immunotherapy are important factors in HCC. More research is still needed to fully understand the profound roles that m⁶A writer Wilms tumor 1-associated protein (WTAP) and CD8⁺ T cells play in the antitumor immunity that prevents HCC from progressing. According to the findings of our investigation, WTAP was significantly elevated in HCC cells and was associated with a poor prognosis. Functionally, WTAP accelerated HCC immune evasion and aerobic glycolysis while suppressing the tumor-killing ability of CD8⁺ T cells. On the other hand, WTAP knockdown had the opposite effect. WTAP targets the m⁶A site on the 3'-UTR of PD-L1 mRNA, which mechanistically increases the stability of PD-L1 mRNA. These results showed that WTAP inhibited CD8⁺ T cells' antitumor activity, which in turn deteriorated HCC immune evasion and aerobic glycolysis. In conclusion, our research uncovers a novel mechanism for WTAP on the tumor-killing ability of CD8⁺ T cells, which helps to overcome HCC immune evasion.

Keywords: Aerobic glycolysis; Hepatocellular carcinoma; Immune evasion; N6-methyladenosine; PD-L1.