Metabolic-immune microenvironment crosstalk mediating ICI resistance in MASH-HCC.

Abstract

As a pivotal immunotherapy modality, immune checkpoint inhibitors (ICIs) have demonstrated significant clinical efficacy in a variety of malignant tumors, including viral hepatocellular carcinoma (HCC). However, metabolic-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) is significantly resistant to ICI, its metabolic-immune crosstalk mechanisms have not been systematically defined, and methods to improve the efficacy of ICI in this context are lacking. Thus, here we elucidate the microenvironmental features of MASH-HCC, focusing on tumor metabolic-immune crosstalk mechanisms such as metabolic reprogramming, metabolic stress, fibrosis, and the gut-liver axis, and summarize clinical and preclinical studies currently assessing whether metabolic drugs may help with overcoming ICI resistance and improving clinical efficacy against MASH-HCC.