Hypomethylation-enhanced CRTC2 Expression Drives Malignant Phenotypes and Primary Resistance to Immunotherapy in Hepatocellular Carcinoma

The cyclic AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a crucial regulator of hepatic lipid metabolism and gluconeogenesis and correlates with tumorigenesis. However, the mechanism through which CRTC2 regulates hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that increased CRTC2 expression predicted advanced tumor grade and stage, as well as worse prognosis in patients with HCC. DNA promoter hypomethylation led to higher expression in HCC. Functionally, contributed to HCC malignant phenotypes through the activated Wnt/β-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939. Moreover, facilitated tumor growth while concurrently downregulating the PD-L1/PD-1 axis, resulting in primary resistance to immunotherapy. In immunocompetent mice models of HCC, targeting in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting might be a promising therapeutic strategy to sensitize immunotherapy in HCC.