Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer

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Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer

Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer

Ferroptosis is a recently discovered form of programmed cell death that plays a significant role in tumor biology and therapy. This unique cell death mechanism is characterized by iron-dependent lipid peroxidation and is precisely regulated by metabolic networks involving lipids, iron, and amino acids.

Different tumors exhibit varying sensitivities to ferroptosis. Recent evidence suggests that triple-negative breast cancer (TNBC)—a highly invasive and treatment-resistant disease—appears particularly susceptible to ferroptosis inducers. This indicates that this new form of non-apoptotic cell death could be an attractive target for treating “refractory” tumors.

Interestingly, ferroptosis has been linked to T-cell-mediated anti-tumor immunity and impacts the effectiveness of tumor immunotherapy. A better understanding of this iron-dependent cell death could help identify new combinational cancer treatment strategies, offering significant biological and clinical implications.

Molecular Mechanisms of Ferroptosis

Ferroptosis is regulated by iron-dependent lipid peroxidation. The three key characteristics of ferroptosis are membrane lipid peroxidation, intracellular iron availability, and the loss of antioxidant defenses.

Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer

Lipid Peroxidation:

Lipid peroxidation disrupts the lipid bilayer and damages membranes, ultimately leading to cell death. Cell membranes rich in polyunsaturated fatty acid (PUFA)-containing phospholipids (PLs) are particularly vulnerable to ROS-induced peroxidation. The availability of membrane PUFAs susceptible to peroxidation is critical for ferroptosis.

PUFAs must be synthesized, activated, and integrated into membrane PLs to participate in this lethal process, requiring two key enzymes: acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). ACSL4 catalyzes the binding of long-chain PUFAs to Coenzyme A (CoA), while LPCAT3 facilitates the esterification and incorporation of these products into membrane phospholipids.

Certain lipoxygenases (LOX) are believed to be the primary enzymes that directly oxidize PUFA-containing lipids in the membrane bilayer. However, the LOX-mediated ferroptosis induction mechanism requires further research. Another enzyme, cytochrome P450 oxidoreductase (POR), has been recently implicated in initiating lipid peroxidation.

Iron Accumulation:

As implied by the term “ferroptosis,” iron is essential for this cell death process. Iron is a critical component of the Fenton reaction, which generates free radicals and mediates lipid peroxidation. Additionally, iron is necessary for activating iron-containing enzymes such as LOX and POR, which are responsible for oxidizing membrane PUFAs. Furthermore, iron plays a crucial role in redox metabolism, contributing to reactive oxygen species (ROS) production within the cell.

Given the critical role of iron in ferroptosis, the cellular iron pool is tightly regulated through genes that control iron storage, release, import, and export within the cell. Changes in labile iron levels affect a cell’s sensitivity to ferroptosis. For example, increased transferrin-mediated iron uptake or degradation of iron storage proteins can enhance iron availability and render cells more susceptible 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 the key antioxidant enzyme that directly eliminates lipid hydroperoxides from the lipid bilayer, preventing the accumulation of lethal lipid ROS.

GPX4 uses glutathione (GSH) as a substrate to reduce membrane lipid hydroperoxides to harmless lipid alcohols. The synthesis of GSH, essential for GPX4 activity, requires three amino acids: cysteine, glycine, and glutamate. Cysteine, the rate-limiting substrate for GSH synthesis, is an important component regulated by the xc- system, comprising the SLC7A11 and SLC3A2 subunits. Small molecule inhibitors like erastin can inhibit SLC7A11-mediated cystine uptake, inducing ferroptosis in various cancers.

A newly discovered alternative GPX4-independent ferroptosis suppression mechanism involves the ferroptosis suppressor protein 1 (FSP1)-CoQ system, which protects cells from GPX4 inhibition-induced ferroptosis. FSP1 can prevent lipid peroxidation by reducing lipid radicals. Thus, cells use two pathways, the cysteine-GSH-GPX4 axis and the FSP1-CoQ axis, to inhibit lipid peroxidation and prevent ferroptosis. When these antioxidant defense systems are overwhelmed by iron-dependent lipid ROS accumulation, ferroptosis occurs.

Ferroptosis and TNBC

Different types of cancers vary in their sensitivity to ferroptosis. Recent evidence indicates that TNBC exhibits altered gene expression in ferroptosis-associated metabolic pathways (such as lipid, iron, and amino acid metabolism), making this treatment-resistant tumor intrinsically susceptible to ferroptosis. TNBC’s unique sensitivity to ferroptosis highlights this non-apoptotic death pathway as an attractive drug target for TNBC.

Lipid Metabolism:

Disruption of lipid metabolism can lead to lipid peroxidation and ferroptosis, with ACSL4 being a critical component in executing ferroptosis. Interestingly, studies have shown that ACSL4 is preferentially expressed in TNBC compared to other breast cancer types, and its expression can predict sensitivity to ferroptosis. A recent study also observed significantly higher ACSL4 expression in TNBC tumors and cell lines. Given that ACSL4 enriches the cell membrane with long-chain PUFAs, this suggests that TNBC is particularly sensitive to ferroptosis due to its PUFA-rich nature.

Iron Metabolism:

Sufficient intracellular iron is a necessary condition for executing ferroptosis. Compared to normal cells, cancer cells exhibit a higher dependency on iron to promote growth. A recent study showed that genes regulating intracellular iron levels are significantly overexpressed in TNBC compared to non-TNBC tumors and cell lines. Specifically, low levels of iron export proteins and high levels of transferrin receptor expression were observed in TNBC. These changes in gene expression involved in iron metabolism regulation may contribute to an increased labile iron pool, promoting iron-dependent lipid peroxidation and making TNBC an iron-rich tumor prone to ferroptosis.

Amino Acid Metabolism:

Amino acid metabolism is critical for the antioxidant defense system comprising SLC7A11-mediated cystine uptake, GSH biosynthesis, and GPX4 activity. Cancer cells may exhibit altered dependency on specific amino acid metabolic pathways. An early study found that TNBC is highly dependent on glutamine metabolism, which supplies SLC7A11, suggesting a potential link between TNBC and ferroptosis.

Additionally, compared to non-TNBC tumors, TNBC tumors have lower expression of GSH synthetase (GSS), a key enzyme in GSH synthesis. GPX4 expression is also lower in TNBC compared to other breast cancer types. Low intracellular GSH and GPX4 expression may weaken antioxidant defenses, increasing the likelihood of lipid peroxidation and making TNBC particularly sensitive to drugs that promote ferroptosis.

Ferroptosis in Tumor Immunotherapy

Recent findings suggest that ferroptosis contributes to CD8+ T-cell anti-tumor activity and affects the efficacy of anti-PD-1/PD-L1 immunotherapy. Combining immunotherapy with methods that promote ferroptosis, such as radiation therapy and targeted therapy, can produce synergistic effects, enhancing tumor control.

Combining Immunotherapy with Cystine Restriction:

Recent reports indicate that CD8+ T-cells activated by anti-PD-L1 immunotherapy secrete IFN-γ after PD-L1 blockade, promoting tumor cell ferroptosis. Secreted IFN-γ significantly downregulates SLC3A2 and SLC7A11 expression in tumor cells, leading to reduced cystine uptake, enhanced lipid peroxidation, and subsequent ferroptosis. Combining cystine/cysteine inhibitors with anti-PD-L1 can produce effective anti-tumor immunity by inducing ferroptosis.

Combining Immunotherapy with Targeted Therapy:

A recent study suggests that resistance to anti-PD-L1 treatment can be overcome by combining it with a TYR03 receptor tyrosine kinase (RTK) inhibitor that promotes ferroptosis. TYR03 expression was found to increase in tumors resistant to anti-PD-1 therapy. Mechanistically, TYR03 signaling upregulates key ferroptosis genes such as SLC3A2, thereby inhibiting tumoricidal ferroptosis. In TNBC syngeneic mouse models, inhibiting TYR03 promotes ferroptosis and sensitizes tumors to anti-PD-1 therapy. This study reveals that lifting ferroptosis inhibition using a TYR03 inhibitor is an effective strategy to overcome immunotherapy resistance.

Combining Immunotherapy with Radiotherapy:

Recent evidence suggests that the synergy between radiotherapy and immunotherapy is related to increased sensitivity to ferroptosis. Radiation has been shown to induce ferroptosis, and genetic and biochemical features of ferroptosis have been observed in irradiated cancer cells. The mechanism involves radiation-induced ROS generation and ACSL4 upregulation, leading to enhanced lipid synthesis, increased lipid peroxidation, and subsequent membrane damage. Therefore, radiotherapy’s anti-tumor effects can be attributed not only to DNA damage-induced cell death but also to ferroptosis induction. Radiotherapy synergizes with immunotherapy to downregulate SLC7A11, mediated by ATM activation and IFN-γ, leading to reduced cystine uptake, increased ferroptosis, and enhanced tumor control. These studies reveal that ferroptosis is a novel mechanism underlying the synergy between radiation and immunotherapy.

Challenges in Targeting Ferroptosis:

Since ferroptosis relies on intracellular iron accumulation, one key challenge in targeting ferroptosis is ensuring iron delivery to tumor cells in vivo. One approach is to use nanoparticle systems, which allow for iron delivery and targeted therapy simultaneously. For instance, nanoparticles can induce ferroptosis by delivering iron-containing agents or ferroptosis inducers directly to tumor cells.

Another challenge is the specific regulation of ferroptosis in vivo, as the immune system’s dynamic response during tumor treatment could affect treatment efficacy. For instance, CD8+ T-cells can promote tumor cell ferroptosis, but the tumor microenvironment may also activate immune suppressor cells such as macrophages, which could release anti-inflammatory cytokines like IL-10 to protect tumors from ferroptosis. Therefore, understanding the complex interaction between ferroptosis and the immune response will be critical for developing successful therapeutic strategies.

Conclusion

Ferroptosis is a unique cell death pathway associated with metabolic disorders, particularly lipid and iron metabolism. Given that TNBC exhibits specific sensitivities to ferroptosis, therapeutic strategies that induce this iron-dependent cell death offer great potential for treating this disease. Combining these approaches with tumor immunotherapy can further enhance anti-tumor efficacy. The application of ferroptosis-inducing agents in anti-tumor immunity has significant clinical implications and deserves further exploration.

Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer

Reference:

1.Ferroptosis: a promising target for cancer immunotherapy. Am J Cancer Res. 2021; 11(12): 5856–5863.

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Tags: cancer immunotherapy tumor

Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer

Targeting Ferroptosis: A Novel Approach to Enhancing Tumor Immunotherapy in Triple-Negative Breast Cancer