Targeting Ferroptosis-Mediated Tumor Microenvironment Remodeling in Hepatocellular Carcinoma: Therapeutic Resistance and Clinical Translation.

Abstract

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide, largely because of marked etiological and molecular heterogeneity, an immunosuppressive tumor microenvironment (TME), high recurrence rates, and resistance to systemic and locoregional therapies. As the liver is central to iron handling, lipid metabolism, glutathione homeostasis, and oxidative stress regulation, ferroptosis has emerged as a biologically relevant vulnerability in HCC. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and restrained by antioxidant defense systems, including the SLC7A11-GSH-GPX4 axis, NRF2 signaling, and parallel ferroptosis-suppressive pathways. Because ferroptosis can promote tumor-cell elimination yet also drive hepatocyte injury, immune suppression, and stromal inflammation, its TME effects are bidirectional. This review asks which cellular compartments benefit or suffer from ferroptotic stress, how etiology and iron redistribution shape therapeutic responses, and how tumor-selective intervention can be translated safely in cirrhotic patients. This review provides a TME-centered synthesis of ferroptosis in HCC, emphasizing how ferroptotic signaling interacts with immune cells, stromal components, metabolic remodeling, angiogenesis, and inflammatory liver injury. We discuss the role of ferroptosis in resistance to targeted therapy, radiotherapy, transarterial therapy, and immunotherapy, and summarize emerging strategies involving natural compounds, chemical ferroptosis inducers, nanomedicine-based delivery systems, predictive biomarkers, and rational combination regimens. Finally, we highlight key translational challenges, including tumor-selective ferroptosis induction, protection of non-malignant liver tissue, biomarker validation, and safety evaluation in clinically relevant models. Understanding ferroptosis-mediated TME remodeling may provide new opportunities to overcome therapeutic resistance and improve outcomes for patients with HCC.

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