Metabolic dysfunction-associated steatotic liver disease and immune checkpoint inhibitor response in gastrointestinal liver metastases: current evidence and future directions.

Liver metastasis is associated with reduced benefit from immune checkpoint inhibitors (ICIs) in several gastrointestinal cancers, yet the background liver status is rarely considered in immunotherapy biomarker studies. Here, we examine whether metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) may alter the immune environment of liver metastases and affect ICI efficacy. The available evidence is strongest, and most mechanistic, for colorectal liver metastasis and derives largely from preclinical models; it is emerging for pancreatic ductal adenocarcinoma and limited for gastric and biliary tract cancers. MASLD and MASH should not be treated as interchangeable: simple steatosis, active steatohepatitis, fibrosis, and cirrhosis represent distinct liver conditions with different possible effects on hepatic seeding and immune-cell access. Early steatohepatitic inflammation may promote hepatic colonization through lipid availability, hepatocyte stress, and myeloid-cell recruitment, whereas advanced fibrosis can reduce initial colonization while impairing lymphocyte access to established lesions. ICI efficacy requires viable tumor-reactive T cells, relief from myeloid-cell suppression, and direct tumor-T-cell contact; MASLD- and MASH-related liver changes may interfere with each of these requirements through mechanisms beyond checkpoint-ligand expression alone. We distinguish T-cell exhaustion from liver metastasis-associated T-cell deletion, and highlight macrophage-mediated elimination of tumor-specific CD8-positive T cells, myeloid chemokine signaling-driven suppressor-cell recruitment, and stromal remodeling as candidate mechanisms, supported mainly by preclinical evidence, that may reduce ICI response. These mechanisms remain unvalidated as predictors of ICI response in cohorts with MASLD/MASH staging. Future studies should assess liver fat, inflammatory activity, fibrosis stage, tumor genotype, and ICI outcomes in the same patients to test whether MASLD/MASH stage is associated with differential benefit.