What is the mechanism of tumor immunotherapy targeting ferroptosis?
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What is the mechanism of tumor immunotherapy targeting ferroptosis?
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What is the mechanism of tumor immunotherapy targeting ferroptosis?
Ferroptosis is a recently discovered type of programmed cell death that plays an important role in tumor biology and therapy.
This unique form of cell death, characterized by iron-dependent lipid peroxidation, is precisely regulated by cellular metabolic networks including lipid, iron, and amino acid metabolism.
Different tumors have different susceptibility to ferroptosis. Recent evidence suggests that triple-negative breast cancer ( TNBC ), a highly aggressive disease with limited treatment options, is particularly susceptible to inducers of ferroptosis, suggesting that this new form of non-apoptotic cell death is therapeutic” an attractive target for refractory tumors.
Interestingly, ferroptosis has recently been linked to T cell-mediated antitumor immunity and affects the efficacy of tumor immunotherapy.
Therefore, a better understanding of this iron-dependent cell death will facilitate the discovery of novel cancer combination therapy strategies, with important biological and clinical implications.
Molecular mechanism of ferroptosis
Ferroptosis is a regulated cell death caused by iron-dependent lipid peroxidation.
Three key features of ferroptosis have been deciphered: membrane lipid peroxidation, intracellular iron availability and loss of antioxidant defenses.
lipid peroxidation
Lipid peroxidation leads to disruption of the lipid bilayer and damage to the membrane, followed by cell death.
Cell membranes are rich in phospholipids ( PLs ) containing polyunsaturated fatty acids ( PUFAs ) and are highly susceptible to ROS-induced peroxidation.
The availability of membrane PUFAs capable of withstanding peroxidation is critical for ferroptosis.
Polyunsaturated fatty acids need to be synthesized, activated and integrated into membrane PLs to participate in this lethal process, which requires two key enzymes, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 ( LPCAT3 ).
ACSL4 catalyzes the attachment of long-chain polyunsaturated fatty acids to coenzyme A ( CoA ), and LPCAT3 facilitates the esterification and incorporation of these products into membrane phospholipids.
Certain lipoxygenases ( LOXs ) are considered to be the main enzymes that can directly oxidize PUFA-containing lipids in membrane bilayers.
However, the mechanism of LOX-mediated ferroptosis induction remains to be further investigated. Another enzyme, cytochrome P450 oxidoreductase ( POR ), was recently implicated in initiating lipid peroxidation.
iron accumulation
As the name “ferroptosis” suggests, iron is required to execute cellular ferroptosis. Iron is an essential element for the Fenton reaction, which generates free radicals and mediates lipid peroxidation.
Furthermore, iron is required for the activation of the iron-containing enzymes LOX and POR, which are responsible for the oxidation of membrane PUFAs.
In addition, iron is very important for redox metabolic processes involved in the production of cellular reactive oxygen species.
As iron plays a key role in the onset of ferroptosis, cellular iron pools are under complex control through the regulation of genes involved in intracellular iron storage, release, import, and export. Changes in cellular labile iron affect cellular susceptibility to ferroptosis.
For example, increased iron import into transferrin or degradation of iron storage proteins has been reported to increase cellular iron utilization and sensitize cells to ferroptosis.
loss of antioxidant capacity
Under normal conditions, iron-mediated lipid oxidation is tightly controlled by the cellular antioxidant defense system.
Glutathione peroxidase 4 ( GPX4 ) is considered a key antioxidant enzyme that acts directly to eliminate hydroperoxides in lipid bilayers and prevent the accumulation of lethal lipid ROS.
GPX4 reduces membrane phospholipid hydroperoxides to harmless lipid alcohols using glutathione ( GSH ) as a substrate.
GSH synthesis is required for GPX4 activity and requires three amino acids: cysteine, glycine, and glutamic acid. Cysteine is the rate-limiting substrate for glutathione synthesis and is an important component of glutathione synthesis.
The abundance of cysteine in mammalian cells is mainly regulated by two subunits of the Xc system, SLC7A11 and SLC3A2. Small molecule inhibitors such as erastin, which inhibits SLC7A11-mediated cystine import, can induce ferroptosis in a variety of cancers.
An alternative GXP4-independent mechanism of ferroptosis suppression has recently been discovered.
The ferroptosis suppressor protein 1 ( FSP1 )-CoQ system is able to protect cells from GPX4 inhibition-induced ferroptosis. FSP1 prevents lipid peroxidation by reducing lipid free radicals.
Thus, cells utilize two pathways, the cysteine-GSH-GPX4 and FSP1 CoQ axes, to inhibit lipid peroxidation and prevent ferroptosis.
Ferroptosis occurs when these antioxidant defenses are overwhelmed by iron-dependent accumulation of lipid ROS.
Ferroptosis and TNBC
Sensitivity to ferroptosis varies widely among different types of cancer.
Recent evidence suggests that gene expression associated with ferroptosis-related metabolic pathways ( such as lipid, iron, and amino acid metabolism ) is altered in TNBC, rendering this refractory tumor intrinsically susceptible to ferroptosis.
The exceptional sensitivity of TNBC to ferroptosis highlights the attractiveness of this non-apoptotic death pathway as a drug target for TNBC.
Fat metabolisim
Dysregulation of lipid metabolism can lead to lipid peroxidation and ferroptosis, and ACSL4 is an important component of ferroptosis execution.
Interestingly, the study found that ACSL4 is preferentially expressed in TNBC compared with other types of breast cancer, and its expression predicts its susceptibility to ferroptosis.
A recent study also observed significantly high expression of ACSL4 in TNBC tumors and cell lines. Given that ACSL4 enriches the cell membrane for long-chain PUFAs, it is suggested that TNBCs are PUFA-rich and therefore particularly sensitive to ferroptosis.
iron metabolism
Sufficient intracellular iron is necessary to execute ferroptosis. Compared with normal cells, cancer cells exhibit a higher dependence on iron for growth.
A recent study showed that genes regulating intracellular iron levels were significantly overexpressed in TNBC compared with non-TNBC tumors and cell lines. In particular, abundant low-level iron export transporters were observed in TNBC, accompanied by high-level expression of iron-import transferrin receptors.
These alterations in the expression of genes involved in the regulation of iron metabolism may contribute to the increase of unstable iron pools in cells, promote iron-dependent lipid peroxidation, and make TNBC an iron-rich tumor prone to ferroptosis.
amino acid metabolism
Amino acid metabolism is critical for an antioxidant defense system consisting of SLC7A11-mediated cystine uptake, GSH biosynthesis, and GPX4 activity.
Cancer cells may exhibit altered dependence on specific amino acid metabolic pathways, and an early study found that, compared with other types of breast cancer, TNBC exhibited a marked dependence on glutamine metabolism required for SLC7A11 supplementation, suggesting that TNBC is associated with iron potential link to death.
In addition, the expression of GSH synthase ( GSS ), which is one of the key enzymes of GSH synthesis, was decreased in TNBC tumors compared with non-TNBC tumors .
GPX4 expression was also lower in TNBC compared with other types of breast cancer.
Low intracellular GSH and GPX4 expression may impair antioxidant defenses, increase the likelihood of lipid peroxidation, and render TNBC particularly sensitive to drugs that promote ferroptosis.
Ferroptosis in tumor immunotherapy
It was recently found that ferroptosis contributes to the antitumor effect of CD8+ T cells and affects the efficacy of anti-PD-1/PD-L1 immunotherapy.
Combining immunotherapy with ferroptosis-promoting modalities, such as radiation therapy and targeted therapy, can produce synergistic effects through ferroptosis to promote tumor control.
Combination of Immunotherapy and Cystine Restriction
It has recently been reported that CD8+ T cells activated by anti-PD-L1 immunotherapy promote tumor cell ferroptosis by secreting IFN-γ after PD-L1 blockade.
Secreted IFN-γ significantly downregulated the expression of SLC3A2 and SLC7A11 in tumor cells, resulting in decreased cystine uptake, enhanced lipid peroxidation, and subsequent ferroptosis.
Cystine/cysteinase synergizes with anti-PD-L1 to generate potent antitumor immunity by inducing ferroptosis.
Immunotherapy combined with targeted therapy
A recent study showed that resistance to anti-PD-L1 therapy can be overcome by combining it with a TYR03 receptor tyrosine kinase ( RTK ) inhibitor, which promotes ferroptosis.
Increased expression of TYR03 was found in anti-PD-1 resistant tumors.
Mechanistically, the TYR03 signaling pathway upregulates the expression of key ferroptosis genes such as SLC3A2, thereby inhibiting tumor ferroptosis. In a syngeneic mouse model of TNBC, inhibition of TYR03 promoted ferroptosis and sensitized tumors to anti-PD-1 therapy.
This study reveals that abrogating ferroptosis by using TYR03 inhibitors is an effective strategy to overcome immunotherapy resistance.
Immunotherapy combined with radiotherapy
Recent evidence suggests that synergistic effects of radiotherapy and immunotherapy are associated with increased susceptibility to ferroptosis.
Radiation has been shown to induce ferroptosis, and genetic and biochemical signatures of ferroptosis have been observed in irradiated cancer cells.
The mechanism involves radiation-induced ROS generation and upregulation of ACSL4, leading to enhanced lipid synthesis, increased lipid peroxidation, and subsequent membrane damage.
Therefore, the antitumor effect of radiotherapy can be attributed not only to DNA damage-induced cell death, but also to the induction of ferroptosis.
Radiotherapy and immunotherapy synergistically downregulate SLC7A11, mediated by the DNA damage-activated kinase ATM and IFN-γ, resulting in reduced cystine uptake, increased ferroptosis, and enhanced tumor control.
These studies reveal ferroptosis as a novel mechanism for the synergistic effect of immunotherapy and radiotherapy.
Combination of Immunotherapy and T Cell Ferroptosis Inhibitors
In addition to inducing tumoral ferroptosis, T cells themselves may undergo ferroptosis, which may attenuate their immune response.
T cells lacking GPX4 rapidly accumulate membrane lipid peroxides and undergo ferroptosis.
Similar to cancer cells, ACSL4 is also essential for ferroptosis of CD8+ T cells and their immune function.
Recently, two studies demonstrated increased expression of CD36 in CD8+ tumor-infiltrating lymphocytes.
T cell-intrinsic CD36 promotes the uptake of oxidized lipids and induces lipid peroxidation, which leads to CD8+ T cell dysfunction.
These findings reveal CD8+ T cell ferroptosis as a novel mode of tumor immunosuppression and highlight the therapeutic potential of blocking CD36 to enhance antitumor immunity.
Notably, this study also demonstrated that GPX4 plays a role in regulating the antitumor function of CD8+ TILs.
Therefore, therapeutic induction of ferroptosis in cancer cells by GPX4 inhibitors may have unwanted on-target effects on T cells and produce undesirable toxicity.
Summary
Ferroptosis is driven by oxidation of PUFA- containing lipids, accumulation of intracellular iron, and loss of antioxidant defenses. Regulation of ferroptosis has a role in various cancer types including TNBC.
In particular, TNBC exhibits a unique expression pattern of ferroptosis-related genes, making it particularly susceptible to ferroptosis inducers.
Therefore, targeting ferroptosis may be a promising therapeutic strategy for this refractory tumor.
In addition, ferroptosis plays an important role in T cell-mediated antitumor immunity, affecting the effect of immunotherapy.
Direct or indirect induction of ferroptosis, such as radiotherapy and targeted therapy, has become a promising combination modality to improve anti-PD-1/PD-L1 immunotherapy.
Therefore, it is necessary to further explore the regulation of ferroptosis combined with immunotherapy.
These findings will broaden and deepen our understanding of this novel form of cell death and provide new opportunities for future research directions.
references:
1. Ferroptosis: a promising target for cancer immunotherapy. Am J Cancer Res. 2021; 11(12): 5856–5863.
https://pubmed.ncbi.nlm.nih.gov/35018229/
What is the mechanism of tumor immunotherapy targeting ferroptosis?
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