Targeting ferroptosis as a vulnerability in cancer

Abstract

Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.

Figure 1.. Ferroptosis-driving and -defence mechanisms.

a. Ferroptosis reflects an antagonism between prerequisites for ferroptosis and ferroptosis-defence systems. The prerequisites for ferroptosis consist of polyunsaturated fatty acid-containing phospholipid (PUFA-PL) synthesis and peroxidation, iron metabolism and mitochondrial metabolism. Ferroptosis-defence systems mainly include the glutathione peroxidase 4 (GPX4)–reduced glutathione (GSH) system, the ferroptosis suppressor protein-1 (FSP1)–ubiquinol (CoQH₂) system, the dihydroorotate dehydrogenase (DHODH)–CoQH₂ system, and the GTP cyclohydroxylase-1 (GCH1)– tetrahydrobiopterin (BH₄) system. When ferroptosis-promoting cellular activities significantly exceed the detoxification capabilities provided by ferroptosis defence systems, a lethal accumulation of lipid peroxides on cellular membranes lead to subsequent membrane rupture and ferroptotic cell death. b. Acyl-coenzyme A synthetase long chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) mediate the synthesis of PUFA-PLs, which are susceptible to peroxidation through both nonenzymatic and enzymatic mechanisms. Iron initiates the nonenzymatic Fenton reaction and acts as an essential cofactor for arachidonate lipoxygenases (ALOXs) and cytochrome P450 oxidoreductase (POR), which promote lipid peroxidation, and mitochondrial metabolism promotes the generation of reactive oxygen species (ROS), ATP, and/or PUFA-PLs. Excessive accumulation of lipid peroxides on cellular membranes can trigger ferroptosis. Cells have evolved at least 4 defence systems with different subcellular localizations to detoxify lipid peroxides and thus protect cells against ferroptosis, wherein cytosolic GPX4 (GPX4^cyto) cooperates with FSP1 on the plasma membrane (and other non-mitochondrial membranes) and mitochondrial GPX4 (GPX4^mito) with DHODH in the mitochondria to neutralize lipid peroxides. The subcellular compartment in which the GCH1–BH₄ system operates remains to be defined. CoQ, coenzyme Q (also known as ubiquinone).

Figure 2.. Ferroptosis as a vulnerability in cancer.

a. Therapy-resistant cancer cells with specific cellular states are vulnerable to ferroptosis, for example cancer cells with a mesenchymal phenotype that are enriched in polyunsaturated fatty acids (PUFAs) owing to high expression of zinc finger E-box binding homeobox 1 (ZEB1), elongation of very long-chain fatty acid protein 5 (ELOVL5) or fatty acid desaturase 1 (FADS1). Similarly, dedifferentiated subtypes of melanoma cells are characterized by PUFA accumulation and a deficiency of reduced glutathione (GSH), which render these cells vulnerable to ferroptosis. In addition, certain cancer cells, such as clear-cell renal cell carcinoma (ccRCC), non-neuroendocrine (NE) small-cell lung cancer (SCLC), and triple-negative breast cancer (TNBC) cells are inherently susceptible to ferroptosis owing to their unique metabolic features, such as high levels of PUFA-containing ether phospholipids (ePLs). b. Mutations in certain tumour suppressors or oncogenes render cancers vulnerable to ferroptosis. Inactivating mutations in any constituent of the tumour-suppressive E-cadherin– neurofibromin 2 (NF2)–Hippo pathway confers a vulnerability to ferroptosis by upregulating Yes-associated protein (YAP)- or transcriptional coactivator with PDZ-binding motif (TAZ)-mediated transcription of ferroptosis-promoting factors, such as acyl-coenzyme A synthetase long chain family member 4 (ACSL4), transferrin receptor 1 (TfR1) and NADPH oxidase 4 (NOX4). In ccRCC, mutation or loss of Von Hippel-Lindau (VHL) promotes hypoxia inducible factor (HIF)-dependent expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA), rendering ccRCCs vulnerable to ferroptosis. Non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations are vulnerable to ferroptosis because of their high dependence on cystine. In another example, isocitrate dehydrogenase 1 (IDH1)-mutated cancer cells with increased levels of the oncometabolite 2-hydroxyglutarate (2-HG) are sensitive to ferroptosis owing to their decreased glutathione peroxidase 4 (GPX4) levels. * indicates either a mutation or loss of the gene, dependent on the gene. c. Vulnerability to ferroptosis is triggered by an imbalance between GPX4-dependent and GPX4-independent ferroptosis defence systems. Cancer cells with low expression of components of GPX4-independent systems (such as ferroptosis suppressor protein-1 (FSP1), dihydroorotate dehydrogenase (DHODH) or GTP cyclohydroxylase-1 (GCH1)) depend on GPX4 for survival and therefore are vulnerable to GPX4 inhibition. Conversely, cancer cells with low expression of GPX4 are sensitive to inactivation of components of GPX4-independent systems. The dashed lines indicate that the function of the indicated protein is diminished or blocked in the corresponding context. PLs, phospholipids.

Figure 3.. The role of ferroptosis in antitumour immunity.

Ferroptosis has a dual role to play in antitumour immunity, dependent on the nature of the immune cell. Boosting antitumour immunity, interferon-γ (IFNγ) secreted by CD8⁺ T cells promotes cancer cell ferroptosis by repressing solute carrier family 7 member 11(SLC7A11) expression in cancer cells. In turn, ferroptotic cancer cells release immunostimulatory signals that promote dendritic cell (DC) maturation and increase the efficiency of macrophages, particularly M1-like tumour-associated macrophages (TAMs), to phagocytose ferroptotic cancer cells. This further strengthens CD8⁺ T cell-mediated tumour suppression. In addition, several types of immunosuppressive cells, including regulatory T (T_reg) cells, myeloid-derived suppressor cells (MDSCs) and M2-like TAMs, are impaired by ferroptosis induction mediated by inhibition of glutathione peroxidase 4 (GPX4) or N-acylsphingosine amidohydrolase 2 (ASAH2), thereby augmenting antitumour immunity. However, CD8⁺ T cells and some T helper (T_H) cell subsets, such as T follicular helper (T_FH) cells, are also susceptible to ferroptosis, which compromises the contribution of ferroptosis to antitumour immunity. The dashed lines indicate that the function of the indicated cell or protein is diminished or blocked in the corresponding context. TCR, T cell receptor.