Hepatocyte-Derived LRG1 Primes the Liver for Metastasis and Impairs Immunotherapy

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.