Abstract The liver undergoes active remodeling by the primary tumor prior to metastatic spread. However, the mechanisms by which hepatocytes dictate the liver-specific tropism of tumors remain elusive. Here, we identify hepatocyte-derived leucine-rich alpha-2-glycoprotein 1 (LRG1) as a key mediator of liver pre-metastatic niche (PMN) formation. LRG1 remodels the hepatic microenvironment by driving immunosuppressive neutrophils accumulation, impairing effect T cell and dendritic cell function, and enhancing angiogenesis in the liver, thereby fostering a pro-metastatic landscape. Clinically, elevated serum LRG1 correlates with existing or impending liver metastases in patients and mouse models. Hepatocyte-specific ablation of LRG1 dampens pre-metastatic niche formation and significantly reduces metastatic burden in vivo. Hepatic LRG1 induced by tumor-associated inflammation via STAT3, promotes liver metastasis through LRG1-driven neutrophil extracellular trap (NET) formation. Importantly, therapeutic blockade of LRG1 not only suppressed liver metastasis but also reprogrammed the hepatic niche toward an immune-activated state, sensitizing tumors to anti-PD-1 therapy. Collectively, our findings reveal a hepatocyte–LRG1 axis that drives liver pre-metastatic niche remodeling and highlight LRG1 as a promising target for the prevention and treatment of liver metastasis.
Wang et al. (Wed,) studied this question.