Tumor microenvironment remodeling following hepatic artery embolotherapy

Hepatic artery embolotherapy (HAE), which includes transarterial embolization and transarterial chemoembolization, is a standard locoregional therapy for unresectable hepatocellular carcinoma (HCC). Beyond inducing ischemic tumor necrosis, HAE profoundly remodels the tumor microenvironment (TME). This review presents current evidence related to HAE-induced TME remodeling and its therapeutic implications. HAE induces a complex network of interconnected hypoxic, nutrient stress, immune, and tissue repair responses, leading to dynamic remodeling of the TME. Hypoxia activates hypoxia-inducible factor-dependent pathways, thereby promoting angiogenesis, metabolic reprogramming, and treatment resistance. Nutrient deprivation induces autophagy, enabling tumor cell survival. Also, HAE exerts dual immunologic effects by stimulating antitumor immunity through tumor antigen release while simultaneously promoting immunosuppressive mechanisms including programmed death-ligand 1 upregulation, accumulation of immunosuppressive macrophages and neutrophils, and reduced cytotoxic T-cell infiltration. Furthermore, tissue repair responses activate hepatic stellate cells and cancer-associated fibroblasts, leading to extracellular matrix deposition, desmoplastic remodeling, and immune exclusion. Emerging preclinical results of several studies suggest that targeting these TME remodeling might enhance the efficacy of HAE. Understanding the dynamic biological responses following HAE might facilitate development of next-generation embolization strategies and rational combination therapies for HCC.