Enhancer Reprogramming of Fibrosis-Associated Monocytic MDSC Confers Intrinsic Resistance of Hepatocellular Carcinoma to Immune Checkpoint Blockade

Hepatocellular carcinoma (HCC), mostly developed in a background of fibrosis/cirrhosis, exhibits relatively low responsiveness to immune-checkpoint blockade (ICB) therapy in recent clinical trials. Whether the fibrotic microenvironment impacts ICB efficacy remains unknown. Here, we show that monocytic myeloid-derived suppressor cell (M-MDSC) accumulation in fibrotic liver is pivotal in restraining tumor-infiltrating lymphocytes (TILs). Hepatic stellate cells (HSCs) induce myeloid-intrinsic p38 MAPK signaling to trigger enhancer reprogramming for M-MDSC development and function. Treatment with p38 MAPK inhibitors abrogated M-MDSC accumulation and prevented HCC development. Furthermore, BET bromodomain inhibition by i-BET762 disrupted HSC-M-MDSC crosstalk to enhance TILs and tumor eradication by ICB, resulting in prolonged host survival. These results demonstrate that enhancer deregulation of M-MDSC by desmoplastic microenvironment modulates tumor sensitivity to ICB.