Metabolic Dysfunction-Associated Steatotic Liver Disease Reprograms the Hepatic Metastatic Niche

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a driver of metastatic progression in the liver. In addition to its association with hepatocellular carcinoma, the steatotic liver supports metastatic colonization from extrahepatic malignancies by altering hepatic metabolism, stromal organization, vascular architecture, and immune surveillance. Clinical and experimental studies show higher rates of liver metastasis and postoperative recurrence for colorectal, pancreatic, and breast cancers in MASLD. The underlying mechanisms are multifactorial. Hepatocyte lipid overload reshapes lipid metabolism and availability, generating lipotoxic stress signals that support the metabolic adaptation of tumor cells. The steatotic liver also promotes extracellular matrix remodeling, hepatic stellate cell activation, sinusoidal capillarization, and the accumulation of immunosuppressive macrophages and exhausted T cells. Tumor- and liver-derived extracellular vesicles further amplify these changes by transporting lipids, cytokines, and microRNAs that establish a permissive premetastatic niche. Although the contribution of hepatic zonation to metastatic outgrowth is poorly characterized, altered zonation likely enhances metastatic fitness by creating spatial gradients in oxygen tension, lipid metabolism, and immune activity. In conclusion, MASLD can reshape the hepatic metastatic microenvironment, which may lead to metabolic- and immune-targeted therapies to treat liver metastasis in patients with MASLD.