What is the molecular mechanisms of Ferroptosis in tumor immunotherapy?
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What is the molecular mechanisms of Ferroptosis in tumor immunotherapy?
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What is the molecular mechanisms of Ferroptosis in tumor immunotherapy?
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 sensitivities to ferroptosis. Recent evidence suggests that triple-negative breast cancer ( TNBC ), a treatment-limited, highly aggressive disease, is particularly susceptible to ferroptosis inducers, suggesting that this new form of non-apoptotic cell death is therapeutic” an attractive target for refractory tumors.
Interestingly, ferroptosis has recently been implicated in 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 new cancer combination therapy strategies, with important biological and clinical implications.
Molecular mechanisms 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, availability of intracellular iron, and loss of antioxidant defenses.
lipid peroxidation
Lipid peroxidation leads to disruption of lipid bilayers and membrane damage, 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 death-death process, which requires two key enzymes, acyl-CoA synthase long-chain family member 4 ( ACSL4 ) and lysophosphatidylcholine acyltransferase 3 ( LPCAT3 ).
ACSL4 is able to catalyze the ligation of long-chain polyunsaturated fatty acids with coenzyme A ( CoA ), and LPCAT3 facilitates the esterification and incorporation of these products into membrane phospholipids.
Certain lipoxygenases ( LOX ) are considered to be the major 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 ), has recently been implicated in initiating lipid peroxidation.
Iron accumulation
As the name “ferroptosis” refers to, iron is required for the execution of cellular ferroptosis. Iron is an integral element of 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 important for redox metabolic processes involved in the production of cellular reactive oxygen species.
Because iron plays a key role in the onset of ferroptosis, cellular iron pools are intricately controlled by regulating genes involved in intracellular iron storage, release, import, and export. Changes in cellular labile iron affect cell susceptibility to ferroptosis.
For example, it has been reported that increased iron input into transferrin or degradation of iron storage proteins can increase cellular iron availability 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 uses glutathione ( GSH ) as a substrate to reduce membrane phospholipid hydroperoxides to harmless lipid alcohols.
The synthesis of GSH 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 an important part of glutathione synthesis.
The abundance of cysteine in mammalian cells is mainly regulated by two subunits of the XC system, the SLC7A11 and SLC3A2 strips. Small molecule inhibitors such as erastin, which inhibit SLC7A11-mediated cystine import, induce ferroptosis in a variety of cancers.
An alternative mechanism of GXP4-independent ferroptosis inhibition was recently discovered. The ferroptosis suppressor protein 1 ( FSP1 )-CoQ system is able to protect cells from ferroptosis induced by GPX4 inhibition.
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 defense systems are overwhelmed by iron-dependent lipid ROS accumulation.
Iron Death 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, making this refractory tumor intrinsically susceptible to ferroptosis.
The specific 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, it was found that ACSL4 is preferentially expressed in TNBC compared to other types of breast cancer, and its expression predicts its sensitivity to ferroptosis.
A recent study also observed that ACSL4 was significantly overexpressed in TNBC tumors and cell lines.
Given that ACSL4 enriches cell membranes with 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 perform ferroptosis. Compared to normal cells, cancer cells exhibit a higher dependence on iron to promote growth.
A recent study showed that genes regulating intracellular iron levels were significantly higher in TNBC compared to non-TNBC tumors and cell lines.
In particular, a large number of low levels of iron-export transporters were observed in TNBC, accompanied by high levels of expression of the iron-import transferrin receptor.
These alterations in the expression of genes involved in the regulation of iron metabolism may contribute to increasing cellular labile iron pools, promoting iron-dependent lipid peroxidation, and making TNBCs iron-rich tumors prone to ferroptosis.
Amino acid metabolism
Amino acid metabolism is critical for the antioxidant defense system consisting of SLC7A11-mediated cystine uptake, GSH biosynthesis, and GPX4 activity.
Cancer cells may exhibit dependent alterations to specific amino acid metabolic pathways, and an earlier study found that TNBC exhibited a marked dependence on glutamine metabolism required for SLC7A11 supplementation compared with other types of breast cancer, suggesting that TNBC is associated with iron A potential link to death.
Furthermore, the expression of GSH synthase ( GSS ), one of the key enzymes in GSH synthesis, was reduced in TNBC tumors compared with non-TNBC tumors .
Expression of GPX4 was also lower in TNBC compared to other types of breast cancer.
Low intracellular GSH and GPX4 expression may impair antioxidant defenses and increase the likelihood of lipid peroxidation, making 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.
Immunotherapy combined with ferroptosis-promoting modalities, such as radiation therapy and targeted therapy, can have a synergistic effect through ferroptosis to promote tumor control.
Combination of immunotherapy and cystine restriction
Recently, it was reported that CD8+ T cells activated by anti-PD-L1 immunotherapy promoted 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 combination 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-induced 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 abolishing ferroptosis by using TYR03 inhibitors is an effective strategy to overcome immunotherapy resistance.
Immunotherapy combined with radiotherapy
Recent evidence suggests that the synergistic effect of radiotherapy and immunotherapy is associated with increased susceptibility to ferroptosis.
Radiation has been shown to induce ferroptosis, and genetic and biochemical signatures of ferroptosis have been observed in radiation-treated cancer cells.
The mechanism involves radiation-induced ROS generation and upregulation of ACSL4, resulting in 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.
Synergistic downregulation of SLC7A11 by radiotherapy and immunotherapy, mediated by the DNA damage-activated kinases ATM and IFN-γ, resulted in decreased cystine uptake, increased ferroptosis, and enhanced tumor control.
These studies reveal ferroptosis as a novel mechanism by which immunotherapy and radiation work synergistically.
Combined application of immunotherapy and T cell ferroptosis inhibitor
In addition to inducing neoplastic ferroptosis, T cells themselves may also undergo ferroptosis, which may attenuate their immune response.
GPX4-deficient T cells 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 have shown that CD36 expression is increased in CD8+ tumor-infiltrating lymphocytes.
T-cell-intrinsic CD36 promotes uptake of oxidized lipids and induces lipid peroxidation, leading to CD8+ T-cell dysfunction. These findings reveal that CD8+ T cell ferroptosis is a novel mode of tumor immunosuppression and underscore the therapeutic potential of blocking CD36 to enhance anti-tumor immunity.
Notably, this study also suggests 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
What is the molecular mechanisms of Ferroptosis in tumor immunotherapy?
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 multiple cancer types including TNBC. In particular, TNBC exhibited a unique expression pattern of ferroptosis-related genes, making it particularly vulnerable 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 and affects the efficacy of immunotherapy.
Direct or indirect induction of ferroptosis, such as radiation therapy and targeted therapy, is a promising combination modality for improving anti-PD-1/PD-L1 immunotherapy.
Therefore, it is necessary to further explore the regulation of ferroptosis in combination with immunotherapy.
These findings will broaden and deepen our understanding of this new form of cell death and provide new opportunities for future research directions.
References:
1.Ferroptosis: a promising target for cancerimmunotherapy. Am J Cancer Res. 2021; 11(12): 5856–5863.
What is the molecular mechanisms of Ferroptosis in tumor immunotherapy?
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