The hepatic macrophage: a key regulator of liver metastatic tumor microenvironment through cell crosstalk

Liver metastasis continues to be a leading cause of cancer-related mortality, particularly in colorectal, pancreatic, and breast cancer. The successful establishment of metastatic lesions depends critically on the liver metastatic tumor microenvironment, where reciprocal cellular interactions between disseminated tumor cells and both parenchymal hepatocytes and non-parenchymal cells facilitate tumor cell colonization and outgrowth. Hepatic macrophages that encompass both tissue-resident Kupffer cells (KCs) and monocyte-derived macrophages (Mo-Macs) have emerged as pivotal regulators of liver metastatic progression. This review summarizes recent progress from the following perspectives: (I) Primary tumors recruit macrophages via secretion of cytokines and exosomes, or induce phenotypic alterations in resident KCs and recruited Mo-Macs, thereby establishing a premetastatic niche; (II) Once the premetastatic niche is formed, hepatic macrophages directly interact with tumor cells to mediate their capture, colonization, and subsequent outgrowth; (III) Furthermore, hepatic macrophages regulate phenotypic changes in T cells, NK cells, hepatocytes, and hepatic stellate cells (HSCs) through cytokine/exosome secretion or direct cell-cell interactions, which induce T cell exhaustion, impairment of NK cell cytotoxicity, and activation of HSCs leading to fibrotic microenvironment formation. Additionally, we review advances in macrophage-targeted therapeutic strategies against liver metastasis. By delineating the pivotal roles of hepatic macrophages in metastatic progression and analyzing current clinical limitations of targeting macrophages for liver metastasis therapies, this review provides foundational insights for understanding macrophage biology and developing effective therapeutics.