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

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.