Iron, Ferroptosis, and Head and Neck Cancer

Abstract

Ferroptosis is an iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species and lipid peroxidation. It plays a critical role not only in promoting drug resistance in tumors, but also in shaping therapeutic approaches for various malignancies. This review aims to elucidate the relationship between ferroptosis and head and neck cancer treatment by discussing its conceptual framework, mechanism of action, functional aspects, and implications for tumor therapy. In addition, this review consolidates strategies aimed at improving the efficacy of head and neck cancer treatment through modulation of ferroptosis, herein serving as a valuable reference for advancing the treatment landscape for this patient population.

Keywords: antitumor strategy; cell death; ferroptosis; head and neck cancer; iron.

Figure 1

The types of cell death. Regulated non-apoptotic forms of cell death include ferroptosis, autophagy, pyroptosis, and necroptosis.

Figure 2

The main regulatory mechanisms of ferroptosis. These mechanisms include the inhibition of the cystine/glutamate antiporter system (system x_c⁻), leading to depletion of intracellular glutathione and the accumulation of lipid peroxidation products due to the oxidation of polyunsaturated fatty acids (PUFAs) by reactive oxygen species (ROS) and the dysregulation of iron metabolism through transferrin receptor 1 (Tf1).

Figure 3

The cross-talk between the immune system (such as CD8⁺ T cells and IFN-γ) and lipid metabolism (such as different fatty acids) in the context of tumor ferroptosis in the tumor microenvironment. In this case, T-cell-derived IFN-γ stimulates ACSL4 and alters tumor cell lipid patterns by binding to arachidonic acid to induce ferroptosis in immunogenic tumor cells [63].