Immunotherapy in liver metastases: Challenges, emerging evidence, and future directions

Table 1 Liver-resident cells and their roles in metastatic colonization and immune suppression

Cell type	Key functions in liver metastasis	Roles in metastatic colonization & immune suppression
KCs[39-46]	Liver-resident macrophages that are the first immune cells to contact CTCs in hepatic sinusoids	Can exert early tumoricidal activity but may become reprogrammed into an immunosuppressive phenotype promoting T-cell exhaustion and MDSC accumulation
LSECs[13-16,47-49]	Fenestrated endothelial cells regulating leukocyte trafficking, antigen presentation, and vascular tone	Under pathological activation, LSECs upregulate adhesion molecules and promote tumor cell arrest, transmigration, and angiogenesis
HSCs[50-55,109]	Perisinusoidal cells that can transition into myofibroblast-like CAFs and remodel ECM	Activated by tumor-derived factors to secrete IL-8, deposit collagen, and create a fibrotic, immune-excluded microenvironment
Hepatocytes[56-61]	Primary parenchymal liver cells central to metabolism and paracrine signaling	Modulate Fas/FasL, IGF2, HGF, and FGL1 to support tumor survival, proliferation, and suppression of CD8+ T-cell and NK-cell responses

KC: Kupffer cell; CTC: Circulating tumor cell; MDSC: Myeloid-derived suppressor cell; LSEC: Liver sinusoidal endothelial cell; HSC: Hepatic stellate cell; CAF: Cancer-associated fibroblast; ECM: Extracellular matrix; IL: Interleukin; FasL: Fas ligand; IGF2: Insulin-like growth factor 2; HGF: Hepatocyte growth factor; FGL1: Fibrinogen-like protein 1; NK: Natural killer.