Ferroptosis: a double-edged sword mediating immune tolerance of cancer

Abstract

The term ferroptosis was put forward in 2012 and has been researched exponentially over the past few years. Ferroptosis is an unconventional pattern of iron-dependent programmed cell death, which belongs to a type of necrosis and is distinguished from apoptosis and autophagy. Actuated by iron-dependent phospholipid peroxidation, ferroptosis is modulated by various cellular metabolic and signaling pathways, including amino acid, lipid, iron, and mitochondrial metabolism. Notably, ferroptosis is associated with numerous diseases and plays a double-edged sword role. Particularly, metastasis-prone or highly-mutated tumor cells are sensitive to ferroptosis. Hence, inducing or prohibiting ferroptosis in tumor cells has vastly promising potential in treating drug-resistant cancers. Immunotolerant cancer cells are not sensitive to the traditional cell death pathway such as apoptosis and necroptosis, while ferroptosis plays a crucial role in mediating tumor and immune cells to antagonize immune tolerance, which has broad prospects in the clinical setting. Herein, we summarized the mechanisms and delineated the regulatory network of ferroptosis, emphasized its dual role in mediating immune tolerance, proposed its significant clinical benefits in the tumor immune microenvironment, and ultimately presented some provocative doubts. This review aims to provide practical guidelines and research directions for the clinical practice of ferroptosis in treating immune-resistant tumors.

Fig. 1. Molecular mechanisms of ferroptosis.

Ferroptosis is typically triggered by iron-dependent lipid peroxidation. The cystine/glutamate transporter (also known as system xc-) imports cystine into cells with a 1:1 counter-transport of glutamate. Once inside the cells, cystine can be oxidated into cysteine, which is used to synthesize GSH. Taken as a reducing cofactor, GSH is in the reaction of reducing lipid hydroperoxides to lipid alcohols under the capability of glutathione peroxidase GPX4. Transsulfuration pathway is involved in supporting the availability of cystine and reduced GSH. Respectively, the mevalonate pathway generates a series of biomolecules and then drives ferroptosis. Several proteins (including serotransferrin, lactotransferrin, Transferrin receptor (TFRC), ferroportin 1 (FPN1), nuclear receptor co-activator 4 (NCOA4)) control ferroptosis through the regulation of iron metabolism. Fe³⁺ could be internalized into cells through three distinct pathways including lactotransferrin, haemin and serotransferrin-TFRC-SLC11A2 pathway, during which Fe³⁺ is reduced and storage in the liable iron pool. Cells have evolved at least four systems inhibiting ferroptosis with different subcellular localizations to decrease lipid peroxides. The GPX4-GSH system can collaborate with FSP1-CoQH2 system on the plasma membrane and can also cooperate with DHODH-CoQH2 system on mitochondrial membrane. Of late, the impact of the hypoxia-inducible factor (HIF) system on fatty acid (FA) metabolism has been depicted. α-KG α-ketoglutarate, AA arachidonic acid, ABCA1 ATP- binding cassette subfamily A member 1, ACSL4 Long- chain fatty acid–CoA ligase 4, ATGL adipose triglyceride lipase (also known as PNPL A2), ALOXs Arachidonate lipoxygenases, CoQ coenzyme Q10, CPT carnitine palmitoyl transferase, DGAT diacylglycerol O- acyltransferase, DPP4 dipeptidyl peptidase 4, ETC electron transport chain, ER endoplasmic reticulum, FLVCR2, FPN1 ferroportin 1 (also known as SLC40A1), GLS glutaminase, GSR glutathione disulfide reductase, GSSG glutathione disulfide, HILPDA hypoxia-inducible lipid droplet- associated, HMGCR HMG-CoA reductase, LOX lipoxygenase, LPCAT lyso-phosphatidylcholine acyltransferase, NCOA4 nuclear receptor co-activator 4, NOX1 NADPH oxidase 1, OGDH oxoglutarate dehydrogenase, OXPHOS oxidative phosphorylation, PE phosphatidylethanolamine, PLIN2 perilipin 2, PS phosphatidylserine, SREBP2 sterol regulatory element binding protein 2, system xc- cystine–glutamate antiporter, TFRC transferrin receptor, GCH1 GTP cyclohydrolase 1, HMOX1 Heme oxygenase, SLC48A1 solute carrier family 48 member 1, SLC46A1 solute carrier family 46 member 1, SLC7A11 solute carrier family 7 member 11, SLC3A2 solute carrier family 3 member 2, SLC11A2 solute carrier family 11 member 2.

Fig. 2. Co-stimulatory, co-inhibitory and checkpoint pathways.

In addition to the co-stimulatory, co-inhibitory and checkpoint pathways, there are other stimulatory and inhibitory pathways (respectively indicated by upward and downward arrows,) that impact the immune response, including tumor necrosis factor (TNF)-related molecules, other members of the CD28 family, adhesion molecules, and T-cell immunoglobulin and Mucin (TIM) molecules. Various stimulatory and inhibitory pathways can affect the onset of ferroptosis in immune cells and tumor cells via a wide range of mechanisms, ultimately facilitating (green plus) or inhibit (red minus) immune tolerance. Moreover, prostate cancer cells could upregulate PD-L1 through HnRNPL over-expression, which in turn inhibits IFN-γ released by CD8 + T cells via the STAT1/SLC7A11/GPX4 signaling axis. Subsequently, the expression of SLC3A2 and SLC7A11 (two subunits of system Xc-) increases, suppressing lipid peroxidation by facilitating cystine uptake, which ultimately contributes to ferroptosis evasion and dampens tumor immunity. Likewise in GBM, activated CD8 + T cells could release IFN-γ, inducing ferroptosis in cancer cells. Fe3O4-siPD-L1@M-BV2, a novel GBM-targeted pharmaceutical delivery system, could stimulate ferroptosis for immunotherapy of drug-resistant GBM and establish a cascade of amplification between ferroptosis and immune activation.