Microenvironment-Driven Reprogramming in Colorectal Cancer Liver Metastasis: Metabolic, Phenotypic, and Immune Adaptation.

Liver metastasis is a major cause of mortality in patients with metastatic colorectal cancer and reflects the selective pressures imposed by the hepatic niche. This review summarizes how the liver microenvironment may reshape disseminated colorectal cancer cells through three interconnected programs: metabolic reprogramming, phenotypic plasticity, and immune evasion. Metabolically, metastatic cells adapt to the glucose-poor and lipid-rich hepatic milieu by switching between glycolysis and oxidative phosphorylation, activating gluconeogenesis, increasing glutamine dependence, and remodeling lipid utilization. Phenotypically, stromal cues such as TGF-β and HGF may promote epithelial-mesenchymal plasticity, thereby supporting invasion, survival, and metastatic outgrowth. Immunologically, the hepatic niche facilitates immune escape through PD-L1 upregulation and the recruitment or polarization of suppressive myeloid and regulatory T-cell populations. We further discuss therapeutic opportunities arising from these vulnerabilities, including inhibition of metabolic dependencies, blockade of TGF-β/FAK-driven plasticity, and combination immunotherapy targeting the PD-1/PD-L1 axis together with the liver immune microenvironment. Finally, we highlight the need for biomarker-guided patient stratification, more faithful preclinical models, and rational combination strategies to overcome adaptive resistance and improve outcomes in colorectal liver metastasis.