PCSK9 in the liver metastatic niche: From cholesterol homeostasis to tumor microenvironment reprogramming

Liver metastasis is a major determinant of cancer mortality, driven not only by tumor-intrinsic traits but also by dynamic reprogramming of the hepatic tumor microenvironment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), classically known for its role in cholesterol metabolism, has recently emerged as a key regulator of this process. Beyond hepatocyte lipid homeostasis, PCSK9 influences multiple liver-resident and infiltrating cell populations, including sinusoidal endothelial cells, hepatic stellate cells, macrophages, and lymphocytes, collectively promoting immune evasion, angiogenic remodeling, vessel co-option, and metastatic progression. Recent preclinical evidence indicates that PCSK9 suppresses antitumor immunity by limiting MHC class I expression, impairing CD8⁺ T-cell infiltration and cytotoxic function and favoring immunosuppressive macrophage and regulatory T-cell programs within the hepatic niche. In parallel, PCSK9 enhances endothelial activation and vascular co-option, contributing to resistance against anti-angiogenic therapies in liver metastases. This work synthesizes current knowledge on PCSK9-mediated regulation of the liver metastatic microenvironment, highlighting its pleiotropic effects across metabolic, vascular, and immune axes. We further discuss emerging therapeutic strategies targeting PCSK9, including clinically approved monoclonal antibodies, siRNA-based approaches, and next-generation nanoparticle delivery systems designed for cell-specific modulation within the liver. These findings position PCSK9 as a central metabolic-immune node linking cholesterol homeostasis to metastatic niche formation. Targeting PCSK9, particularly through precision delivery platforms, represents a promising avenue to enhance antitumor immunity, overcome therapy resistance, and improve outcomes in liver metastasis and primary liver cancers.