NRF2 mutation enhances the immune escape of hepatocellular carcinoma by reducing STING activation

The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor usually hyperactivated in hepatocellular carcinoma (HCC). In addition, about 14 % of HCC patients carry mutation in NRF2 or Kelch-like ECH-associated protein 1 (Keap1), a NRF2 inhibitor, both of which lead to constitutive activation of NRF2. It has been widely reported that NRF2 plays important roles in the proliferation, differentiation and metastasis of tumor cells. But as an important gene involved in antioxidation and anti-inflammation, little studies have focused on its role in tumor immune escape. Here we found that NRF2 gain-of-function mutation leads to reduced expression of STING and decreased infiltration of peripheral immune cells through which way it helps the tumor cells to evade from immune surveillance. This phenomenon can be reversed by STING overexpression. Our study also revealed that NRF2 mutation greatly reduced the effect of STING activating based immunotherapy. It is important to simultaneously inhibit the activity of NRF2 when using STING agonist for the treatment of HCC patients carrying NRF2 mutation.