Ferroptosis contributes to immunosuppression

Abstract

As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term “immunosuppression” refers to various factors that can directly harm immune cells’ structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.

Keywords

ferroptosis / immunosuppression / immune cells

1 Introduction

Ferroptosis, a nonapoptotic form of regulatory cell death, is caused by excessive lipid peroxides and iron-dependent reactive oxygen species (ROS) accumulation [1,2]. It is more immunogenic than apoptosis and differs from other forms of cell death in terms of morphology, biology, and genetics [3]. Ferroptotic cells have a classic necrotic shape with decreased mitochondria cristae, condensed membranes, torn outer membranes, small aberrant mitochondria, and no apoptotic markers.

Ferroptosis is also caused by the regulation of cystine/glutamate reverse transport system ${\mathrm{x}}_{\mathrm{c}}^{-}$, which consists of two subunits linked via a disulfide bond and includes the heavy chain subunit solute carrier family 3 member 2 [4], light chain subunit solute carrier family 7 member 11 (SLC7A11) [5], nuclear factor erythrocyte 2-associated factor 2 (NRF2)-related pathway [6,7], and selenocysteine-containing enzyme glutathione peroxidase 4 (GPX4)-related pathway [8]. Glutathione (GSH) and GPX4 normally prevent the accumulation of toxic lipid peroxides by biochemical reduction [9,10]. GPX4 can also directly reduce oxidized lipoproteins and phospholipid hydroperoxides, protecting cells from membrane lipid peroxidation [11]. Ferroptosis-related regulatory factors and pathways are involved in human diseases, including acute kidney injury [12–14], liver disease [15], neurodegenerative diseases [16–18], cancer [19,20], and cardiovascular diseases [21], such as atherosclerosis, stroke [22–24], ischemic reperfusion injury [25–27], and heart failure [28].

Immunosuppression refers to a variety of chemical and physical factors that can directly harm immune cells’ structure and function, interfere with the neuroendocrine system, or indirectly cause the immune system to produce insufficient response to foreign antigens, rendering it unable to fend off the invasion and eventually result in immunopathological processes. The immune system develops from a wide range of innate and adaptive immune cells, including lymphocytes, natural killer (NK) cells, macrophages, dendritic cells (DCs), T cells, and B cells. Reduced number of lymphocytes, increased number of circulating myeloid-derived immunosuppressive cells (MDSCs), phenotypic changes of immune cells, and reduced or even lost immune cell function all lead to immunosuppression.

Iron metabolism plays an important role in the maturation and differentiation of immune cells. Iron overload and oxidative stress affect the ability of immune cells to polarize and cause some immune cells to die, making the condition worse [29,30]. Furthermore, the ferroptosis pathway controls the malfunction and even death of immune cells in various diseases. For example, iron overload in senescence-associated diseases can result in macrophage ferroptosis and suppress the immune response by lowering the macrophage population. Systemic lupus erythematosus (SLE) suppresses the immunity by inhibiting the GSH content in neutrophils, leading to their ferroptosis [31,32]. Sepsis inhibits the differentiation of bone marrow-derived DCs into mature DCs through the overexpression of ferroptosis-related genes, hence limiting DCs’ ability to kill [33]. In cancer, M2, Treg, B lymphoma cells, and MDSCs with increased ferroptosis resistance are filtered out to suppress antitumor immunity [34–36], and ferroptosis signals are upregulated to impair the function of NK cells and depress the immune system [37]. Therefore, the promoting relationship between ferroptosis and the immunosuppressive microenvironment of various diseases may contribute to the corresponding treatments. However, evidence on how ferroptosis promotes immunosuppression is relatively limited. Oxidative stress and lipid peroxidation are typical features of ferroptosis, and their relationship with immunosuppression can provide basis for our inference. The immune microenvironment is a complex system that requires the participation of multiple immune cells, and the immune cells play a major role vary in different diseases. Therefore, this review analyzes various studies to determine the mechanism of how ferroptosis inhibits the immune system.

2 Ferroptosis impedes macrophage-mediated immune response

Macrophages are phagocytic cells that can internalize large particles, such as debris, apoptotic cells, and pathogens, to maintain homeostasis in the human body. Their ability to recognize and eliminate bacteria is the host’s first line of defense against Gram-negative bacteria, such as mycobacteria and Pseudomonas aeruginosa [38,39]. Moreover, macrophages can polarize their functions in a continuum between these two extremes as they receive and integrate environmental signals [40]. Macrophages can be divided into two major subpopulations: classical macrophage (M1) and alternative macrophage (M2). M1 is polarized by lipopolysaccharide (LPS) alone or in association with type 1 T helper (Th1) cytokines, e.g., interferon γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF), and produces pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). M2 is polarized by type 2 T helper (Th2) cytokines, e.g., IL-4 and IL-13, and produces anti-inflammatory cytokines, e.g., IL-10 and transforming growth factor-β (TGF-β) [41,42]. Macrophages can also be classified by source, such as splenic red marrow macrophages (RPMs), bone marrow-derived macrophages (BMDMs), central nervous system (CNS) resident macrophages, microglia [43], and peritoneal macrophages (PMs) [44].

Erastin [45], the first reagent identified to induce ferroptosis in cells, concentration-dependently inhibits the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNFs, and IL-1 in LPS-stimulated BMDMs, resulting in anti-inflammatory actions in vivo [46] (Fig.1). RAS-selective lethal 3 (RSL3) [8], a well-known ferroptosis inducer, inhibits RNA polymerase II recruitment to the transcription start site of pro-inflammatory cytokine genes by inducing NRF2 protein expression under LPS stimulation. This action prevents cytokine transcription and reduces inflammatory responses in microglia and PMs [47]. These agents are also commonly used to detect ferroptosis resistance in various cells.

Fig.1 Mechanism of ferroptosis in macrophage subtypes. (A) When the content of PUFA-PL in macrophages increases, lipid peroxidation and ferroptosis are likely to occur (path ①, blue arrow). After Mtb enters macrophages, it increases the production of lipid peroxides, which ultimately results in ferroptosis (path ②, red arrow). The excess RBCs are ingested by macrophages, causing an increase in Fe2+ and lipid peroxides and ultimately leading to ferroptosis (path ③, green arrow). Ferritin can increase the amount of Fe2+ and lipid peroxide, ultimately leading to ferroptosis (path ④, black arrow). When recognized by macrophages, SAPE-OOH on the membrane of ferroptotic cells causes an increase in Fe2+ and lipid peroxides, ultimately resulting in ferroptosis (path ⑤, violet arrow). The KRASG120 protein produced by tumor cells interacts with macrophages by AGR, encouraging macrophages to polarize toward M2 (path ⑥, yellow arrow). The 8-OHG released by tumor cells stimulates macrophages to polarize toward M2 by activating the STING1 signaling pathway (path ⑦, black arrow). (B) As a system ${\mathrm{x}}_{\mathrm{c}}^{-}$ (also called cystine/glutamate antiporter system) inhibitor, erastin suppresses cystine and Glu transfer, decreases GSH and GPX synthesis, and increases lipid peroxides, leading to BMDM ferroptosis (path ①, black arrow). Erastin can reduce the expression of iNOS, COX-2, TNF-α, and IL-1β in BMDM stimulated by LPS, thereby reducing the damage of LPS to BMDM function (path ②, green arrow). (C) M1 is more resistant to ferroptosis and have fewer cell deaths than M2 or M0 (black arrow). However, MDCs differentiate into M2 under the influence of ferroptosis, and the overall number of M2 cells remains mostly unaltered (green arrow).

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3 Tumor induces macrophages ferroptosis and polarization

In the tumor microenvironment (TME), the monocytes in the bloodstream are recruited to tumor inflammatory areas and differentiate into tumor-associated macrophages (TAMs), which constitute up to 80% of the total tumor mass and can stimulate cancer cell growth, angiogenesis, and metastasis and inhibit anti-cancer immunity [48–50]. M1 macrophages can phagocytose tumor cells, but M2 macrophages can encourage tumor invasion and growth. In addition, TME-released substances including IL-10, IL-4, and IL-13 can differentiate M1 into M2, which has pro-angiogenic and pro-fibrotic properties and suppresses anti-tumor immunity [51].

Pro-ferroptotic stimulation encourages cancer cells to produce 8-ortho-hydroxygenistein (8-OHG), which activates the STING-dependent DNA sensor pathway in TAMs and causes them to infiltrate and polarize M2 [34,52]. The Kirsten rat sarcoma virus (KRAS)^G12D released by ferroptotic cells induces anterior gradient (AGR)-dependent macrophage M2 polarization by activating the signal transducer and transcription 3 (STAT3)-mediated fatty acid oxidation [34]. The oncogenic KRAS homolog protein in exons produced by ferroptotic tumor cells can encourage M2 polarization in TAM [52], promoting immunosuppression and promoting tumor growth (Fig.1). 8-OHG is not only a product of lipid peroxidation but can also induce ferroptosis [53]. STAT3 can also regulate ferroptosis [54]. Thus, tumor cells can enhance M2 polarization by ferroptosis and suppress immunity.

M1 has a high expression of ferritin and a low expression of ferroportin, which is conducive to iron chelation in macrophages. Meanwhile, M2 exhibits a low expression of ferritin and a high expression of ferroportin, representing an iron-releasing phenotype [55,56]. Therefore, M1 may be more resistant to ferroptosis. Kapralov et al. [57] found that M1 cells display remarkably larger amounts of iNOS and NO radical (NO-) than M2 and resting macrophages, leading to their stronger resistance to ferroptosis induced by GPX4-deficiency. iNOS, producers of nitric oxide and superoxide in cells, can reduce ROS levels [58]. In theory, immunological promotion should occur in the TME because M1 is less susceptible to ferroptosis and M2 is likely to experience ferroptosis. However, M2 is the main component of TAM [49], and the exosomes isolated from M2 macrophages can inject ferritin heavy chain into colon cancer cells to promote cell proliferation [59], leading to immune suppression. The quantity of M2 TAM is unaffected by the absence of iNOS in bone marrow-derived macrophages, and the number of M1 TAM is considerably decreased [57,60] (Fig.1). In the TME, especially when macrophages phagocytose ferroptotic cells with accumulated lipid peroxidation (LPO), ferroptosis likely occurs in M2 cells. However, the reduction in the total number of M2 is not evident in early ferroptosis due to the bone marrow-derived macrophages and polarization of resistant M1 cells, leading to the suppression of anti-tumor immunity.

4 Macrophages undergo ferroptosis by phagocytosis of pathogens

Erythrocyte synthesis requires the highest amount of iron, even in senescent erythrocytes [61]. The main role of erythroid macrophages in the spleen and Kupffer cells in the liver is to actively phagocytose senescent erythrocytes [62]. When the erythroid macrophages in the spleen acutely recycle large amounts of red blood cells (RBCs), intracellular iron accumulation occurs and consequently leads to an increase in reactive oxygen species and lipid peroxidation and eventually ferroptosis [63]. This phenomenon is evident in aged spleen, liver, ovaries, and uterus. The mechanism may be related to the increased expression of Acyl-CoA synthetase long-chain family 4 (ACSL4, a classic marker of ferroptosis) in fatty liver, kidney, and ovary [64–67] and the increased expression of prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2, a typical marker of ferroptosis) in aged spleen, kidney, and ovary [68,69]. Therefore, this transfuse-related immunomodulatory mechanism may trigger the ferroptosis of macrophages. When a large number of macrophages die, a high concentration of lipid peroxides and iron elements stored in the macrophages are released and harm the recruited immune cells, resulting in immunosuppression. To compensate for the large reduction of macrophages, Ly6Chi monocytes migrate from the bone marrow to the spleen and differentiate into splenic RPMs; the remaining spleen RPMs continue to proliferate. Local proliferation and monocyte intracellular flow reduce the damage of ferroptosis to the immune system [63].

Amaral et al. [70] discovered that the phagocytosis of Mycobacterium tuberculosis (Mtb) by macrophage leads to ferroptosis with high lipid peroxidation levels and abundant bone marrow-derived immunosuppressive cells. Furthermore, the IL-1 produced by MDSCs inhibits the differentiation of pluripotent progenitor cells into B lymphocytes [71], causing immunosuppression. In Mtb infections, macrophage necrosis is usually accompanied by extracellular bacterial dissemination [72], causing further damage to the immune system. The biofilm-producing mutant P. aeruginosa induces ferroptosis in human bronchial epithelial (HBE) cells by upregulating pLOXA and oxidizing host cell’s arachidonoyl- (AA) and adrenoyl-phosphatidylethanolamines (PE) to 15-HOOAA-PE in P. aeruginosa-associated diseases, such as cystic fibrosis [73]. The SAPE-OOH on the HBE cell surface is also recognized by the Toll-like receptor (TLR) 2 on the macrophage cell membrane and thus induce ferroptosis in macrophages [74], leading to immunosuppression.

5 Different subtypes of macrophages have different ferroptosis resistance

Cell culture experiment of RSL3/LPS also confirmed that different types of glial cells respond differently to ferroptosis: BV2 microglia cells and PMs are resistant to ferroptosis, and BMDMs and RAW264.7 cells are extremely vulnerable to ferroptosis [75]. As ferroptotic disorders progress, BMDM apoptosis limits macrophage flow and disrupts local self-circulation, leading to a continuous decline in other macrophage types. Finally, the innate immune system’s initial line of defense breaks down. The prudent application of the ferroptosis resistance of various macrophage subtypes under various clinical circumstances may improve the treatment of infections, neurodegenerative diseases, and even tumors.

6 Ferroptosis impedes neutrophil-mediated immune response

Neutrophils are the most abundant white blood cells in human blood and are the first immune cells recruited to respond to infection and injury [76]. They participate in a wide range of effect mechanisms, such as phagocytosis, cytokine release, matrix protease secretion, ROS production, and formation of neutrophil extracellular traps (NETs) [77,78].

7 Stroke induces neutrophil ferroptosis and immunosuppression

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor that regulates the expression of multiple genes and is critical for lipid and glucose metabolism [79]. It also plays anti-oxidative and anti-fibrotic roles in a number of pathophysiological processes [80]. Decreased PPAR-γ expression in chondrocytes can lead to chondrocytes ferroptosis [81]. Therefore, PPAR-γ is most likely associated with ferroptosis. After hyperglycemic stroke, PPAR-γ downregulation in neutrophils leads to the reduced secretion of lactoferrin (LTF), which can cause iron overload and ferroptosis in neurons [24]. LTF, one of the most prevalent proteins released by neutrophils, is a glycoprotein that binds iron strongly and can enter cells through LTF receptors or other receptors to induce immune cells ferroptosis [82–84]. Following a stroke, the brain develops a ferroptotic microenvironment, which will lead to ferroptosis due to neuronal iron overload and inadequate LTF intake. Therefore, neutrophils may undergo the same type of ferroptosis after stroke. However, neutrophils themselves still have a small amount of LTF, so they may be more resistant to ferroptosis than neurons. Furthermore, the deletion of the LTF gene can result in a reduction in the percentage of total B cells, T1 B cells, and follicular cells, which is detrimental to the early stages of B cell differentiation. Therefore, neutrophil ferroptosis caused by LTF after stroke may also lead to B cell immunosuppression. Aging drives early neutrophil differentiation, which raises ROS generation and phagocytosis [85]. Therefore, aging-related neutrophils are highly susceptible to ferroptosis, which may damage the brain immune environment. This finding provides a new theory for the mechanism of neutrophil injury in Alzheimer’s disease and suggests that neutrophil heterogeneity may determine the progression of the disease.

8 SLE induces neutrophil ferroptosis and immunosuppression

Produced by the activation of the Ca²⁺/calmodulin-dependent protein kinase IV/cyclic AMP-responsive element modulator (CaMKIV/CREM) axis and enhanced translocation, the serum autoantibodies for SLE IgG and IFNs can decrease GPX4, increase intracellular lipid ROS, and trigger neutrophil ferroptosis in lupus-susceptible mice and individuals with SLE (Fig.2). This inhibition does not extend to lymphocytes or monocytes but only causes neutrophils to produce additional lipid ROS and lowers cellular activity in patients with SLE [31,32]. Therefore, ferroptosis resistance in neutrophils might be lower than that in lymphocytes and monocytes. Furthermore, the deletion of the LTF gene has resulted in elevated IgG antibody deposition in SLE mice [86], which may enhance neutrophils’ susceptibility to ferroptosis. LTF taken orally helps lessen the symptoms [86]. In summary, neutrophils may cause PPAR-γ/LTF axis ferroptosis in an SLE setting. This action might hasten the disease’s course by decreasing LTF, which in turn leads to B cell malfunction and immune suppression.

Fig.2 Mechanism of ferroptosis in neutrophils. Ferroptotic endothelial cells may release ferritin via exosomes to boost the amount of neutrophilic lipid ROS, which induces ferroptosis (path ①, blue arrow). In SLE, after lgG and IFN-1 are recognized by neutrophils, the CaMKIV/CREM pathway is activated, resulting in a decrease in GPX4 that ultimately leads to ferroptosis in neutrophils (path ②, violet arrow; path ③, black arrow). In stroke, a decrease in neutrophil PPAR-γ expression leads to a decrease in LTF secretion and ultimately an increase in intracellular ROS levels, leading to ferroptosis (path ④, green arrow).

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9 Endothelial cells may induce neutrophil ferroptosis and immunosuppression

Following heart transplantation, IRI causes the ferroptosis of endothelial cells and the production of DAMPs that, via the TLR4/Trif/IFN-1 signaling pathway [87], encourage neutrophil adherence to coronary endothelial cells and then coordinate neutrophil recruitment to the damaged myocardium and amplify myocardial injury [88]. Ferritin exosomes can be secreted by ferroptotic macrophages to spread ferroptosis to endothelial cells and released simultaneously by endothelial cells in a ferroptotic environment [89]. Overload iron is also introduced into neutrophils through disseminated ferritin, impairing their function to suppress the immune system (Fig.2). The first group of neutrophils recruited to the site of injury in bacterial infectious lung disease must also be affected by bacterial infection or ferroptotic macrophages after bacterial infection, resulting in ferroptosis. This phenomenon implies a complex immunosuppressive state.

Despite the limited studies on the interaction between neutrophil and ferroptosis, the findings showed that ferroptosis can depress the immune system by accelerating neutrophil mortality or impairing its activity. Neutrophils may be one type of immune cells that is most sensitive to ferroptosis.

10 Ferroptosis impedes T cell-mediated immune response

T cells are a morphologically and functionally complex subgroup. According to their immune response function, they can be divided into Th, suppressor T (Ts), effector T (Te), and cytotoxic T. Ths are mainly formed by the differentiation and maturation of CD4⁺ T cells under the action of various cytokines and can be further divided into Th1, Th2, Th17, and Treg [90,91]. In vitro studies showed that Th2 cloning encourages B cells to manufacture antibodies (such as IgM, IgA, and IgE) by releasing IL-4, IL-5, and IL-6. Th1 clones produce IFN-γ. Low IFN-γ levels help B cells and induce IgG antibodies (in mice), but high IFN-γ levels inhibit B cell response. The cytokines of a typical proinflammatory cell called Th17 can enhance tumor immunity [92–94]. Treg can prevent the activation or overactivity of autoreactive Th cells [95]. Iron is essential for T cell survival and function: iron deficiency inhibits T cell proliferation, and iron overload leads to an imbalance between CD4⁺ and CD8⁺ T cell ratios, elevated ROS levels, and DNA damage in T cells [96]. Iron is also crucial in the regulation of T cell mitochondrial function [97], thereby suppressing immunity.

11 Ferroptosis helps tumor cells evade T cell immunity

IFN-γ, which can be released by activated CD8⁺ T cells in the TME, makes tumor cells susceptible to certain stimuli [98], including GPX4 or system ${\mathrm{x}}_{\mathrm{c}}^{-}$ and cystine deprivation [99,100], causing ferroptosis in tumor cells. IFN-γ signaling also inhibits macrophage differentiation into tumorigenic M2 [101]. When ferroptosis occurs, the increased expression of fatty acid transposon CD36 on CD8⁺ T cell membrane leads to intracellular fatty acid enrichment or lipid oxidation, impairing the production of cytotoxic cytokines such as TNF-α and TNF-γ and anti-tumor function in vivo [102–104] and ultimately enabling tumor cells to escape ferroptosis.

Triggered ferroptosis in cancer cells is associated with increased the expression of PTGS2, a synthetase of prostaglandin E2 (PGE2), and increased release of PGE2, also a ferroptosis-related factor [105,106]. PGE2 blocks conventional type 1 dendritic cell (CDC1)-dependent CD8⁺ T cell-mediated immune control and directly inhibits cytotoxic T cell action [107]. PGE2 suppresses chemokines CCL5, CXCL10, CXCL11, and CXCL16, which are key to the recruitment of cytotoxic T cells and NK cells [108,109]. Even if the tumor is not able to evade T cell pursuit, it can still hinder T cell function by boosting PGE2 release, which will aid other tumor cells to achieve immunological escape.

Evidence points to ferroptosis as an inhibitor of T cell immunity. The activation of an immune response is likely a result of the body’s cells adapting to a harsh environment. Some cancer cells evade T cell immune response by death ligands. For example, heteronucleoprotein L (HnRNP L) has higher expression in PCa cancer cells than in PCa cells. HnRNP L upregulates the expression of programmed death ligand 1 (PD-L1) by binding to YY1 mRNA and induces T cell impotence after binding with inhibitory receptor programmed cell death protein 1 (PD-1) on T cells, thus inhibiting Jurkat T cell-mediated ferrotosis in castration-resistant prostate cancer cells [110–112] (Fig.3). In addition, tumor cell disintegration can release high levels of 15-hydroxypereicosanotrienoic acid lipoproteins and other LPOs, prompting epithelial and immune cells to quickly trigger ferroptosis [57]. These LPOs have been detected in CD8⁺ T and CD4⁺ T cells derived from tumors but not in lymph nodes, indicating that cancer cells induce ferroptosis by enhancing the sensitivity of activated CD8⁺ T cells and conventional CD4⁺ T cells to ferroptosis [113], thus inhibiting anti-tumor immunity.

Fig.3 Mechanism of ferroptosis in tumor cells and T cells. Ferroptosis activation causes tumor cells to express PTGS2, which in turn increases the synthesis of PGE2 that suppresses T cell activity (path ①, blue arrow). Tumor cells express HNRNP-L; when its protein binds to YY1 mRNA, it increases the expression of PD-L1. PD-1, upon recognition by PD-L1, suppresses T cell proliferation and TNF release, which in turn stimulates the growth of tumor cells (path ②, green arrow). Large amounts of LPOs released from tumor cells cause T cells to undergo ferroptosis by increasing lipid ROS within T cells (path ③, orange arrow). Tumor cells upregulate CD36 on the surface of T cells, which leads to the ferroptosis of T cells due to lipid ROS accumulation (path ④, violet narrow). Tumor cells can also increase the expression of CD36 on the surface of Tregs and the content of fatty acids in the cells. Excess fatty acids enter the TCA cycle metabolism and supply energy for the growth and development of Tregs, thus inhibiting the function of T cells (path ⑤, black arrow).

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12 Tumors screen out Tregs by ferroptosis, leading to immunosuppression

Tregs are part of CD4⁺ T cells, which are typically immunosuppressive. When T cell antigen receptor (TCR) and CD28 are stimulated simultaneously with GPX4-deficient Treg cells, these cells also produced additional mitochondrial superoxide and accumulated lipid peroxide, which are hallmarks of ferroptosis [114]. CD36 expression on the Treg cell membrane also increases [115], resulting in an increase in intracellular lipids. Compared with T cell subtypes, Treg cells are more dependent on fatty acid metabolism and TCA cycle for energy supply [116,117]. FAO upregulation could improve the production of Treg, and FAO damage would impair the differentiation of Treg [118]. Therefore, Tregs have stronger resistance to ferroptosis than other CD4⁺ T cells, maintaining their activity in ferroptosis-related diseases and inhibiting T cell function to suppress the immune response and accelerate the progression of disease (Fig.3).

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) acts as a transmitting inhibitory signal and is important for T cell-related immunity [119]. As a member of the CD28 immunoglobulin subfamily, it is primarily expressed by T cells. It competes with CD28 to bind the CD80/CD86 ligand on the surface of antigen-presenting cells (APCs), inhibits T cell activation [120], and induces Treg development and function [121]. To give DCs immunological tolerance traits, CTLA-4 sends an inhibitory signal to APCs, downregulates CD80/CD86 in DCs, and upregulates indoleamino-2, 3-dioxygenase (IDO) in DCs [122]. Treg cells can also enable DCs to increase the release of PD-L1 through CD80 and further enhance the immunosuppressive effect [123]. In addition, CTLA-4 is highly expressed in tumor-infiltrating Tregs [124,125]. This finding indicates that in the TME, ferroptosis can screen out Tregs by killing other subtypes of T cells and inhibit anti-tumor immunity depending on CTLA-4. CTLA-4 is also highly expressed in hepatocellular carcinoma and is associated with some genes related to ferroptosis [126]. Although the specific mechanism remains unclear, ferroptosis may induce T cell dysfunction by upregulating CTLA-4 in tumor cells and competitively binding to activate T cell surface receptors.

13 Different subtypes of T cells have different ferroptosis resistance

Follicular helper T cells (TFHs), a specific subset of CD4⁺ T cells, are produced when the B cell lymphoma 6 (BCL6) transcription factor is expressed in CD4⁺ T cells [127]. Its primary role in the immune system is to interact with B cells that have taken up and processed antigens at the T: B junction following T cell initiation, induce B cell migration, and initiate germinal center (GC) and extracellular follicular response to protein antigens [128]. Germinal centers play an important role in B cell physiology and malignant tumors and promote humoral immune function [129]. Human TFHs have greater levels of patient-reported outcomes and are more vulnerable to ferroptosis caused by RSL3 than non-TFH cells. They are also more sensitive to ferroptosis with increased intracellular lipid ROS after attaching to BGC cells [130]. In summary, the TFH cells in the CD4⁺ T cell subgroup are the first to undergo ferroptosis as the disease worsens and directly cause the B cell center response to fail, suppressing the humoral immunity of B cells. In addition, Te secrete more of the antioxidant thioredoxin-1 than T cells [131] and produce less superoxides than memory T cells (Tms) that rely on oxidative phosphorylation and have high capacity for extra-mitochondrial energy production [132]. Therefore, effector T cells are sensitive to ferroptosis. In ferroptosis-related diseases, the effector T cells that are capable of killing will be subjected to ferroptosis first, thus severely damaging the immune system.

Hemochromatosis (HH) is a distinct clinicopathological subset of iron overload syndrome characterized by the inability to prevent unwanted iron from entering the circulation pool due to genetic changes that affect the synthesis or activity of hepcidin [133]. According to clinical investigations, patients with HH have significantly low percentages and total numbers of CD8⁺ T and iNKT cells in their peripheral blood. However, no difference in CD4⁺ T cell population and total lymphocyte count was observed [134]. This phenomenon might be attributed to bone marrow-derived cells differentiating less into CD8⁺ T cells and iNKT during the ferroptosis state or may be related to the reduced ability of CD8⁺ T and iNKT to resist ferroptosis. In either case, the immune response is significantly hampered by the decline in CD8⁺ T, the primary killer cell.

Despite the different sensitivities to ferroptosis in T cell subsets, we hypothesize that ferroptosis plays a suppressive role in different T cell populations.

14 Ferroptosis impedes B cell-mediated immune response

B cells can be divided into several subclasses, each with a unique ontogeny, homeostasis, and function. B1 cells can be subdivided divided into B1a cells and B1b cells, and B2 cells can be subdivided into follicular B (Fo B) cells and marginal zone B (MZ B) cells. Fo B cell-related immune responses require the assistance of T cells, and B1 and MZ B cells independently and rapidly react to blood-derived antigens [135–138]. Even in the TME, plasma cells have a considerable production capacity for cytokines and antibodies despite their modest size [139,140], driving antibody-dependent cytotoxicity and phagocytosis to promote anti-tumor immunity [141,142]. IgG⁺ memory B cells can focus on the edge of tumor invasion to produce granzyme B and tumor necrosis factor-related apoptosis-inducing ligand, express the surface markers of adenomatous polyposis coli produce IFN-γ, and cooperate with CD8⁺ T cells for anti-tumor immunity [143].

15 Epstein Barr virus (EBV) screens out lymphoma cell by ferroptosis, leading to immunosuppression

EBV dynamically sensitizes B cells to ferroptosis dynamics. In the early stage of infection, EBV abnormally activates ROS production in B cells, making them sensitive to ferroptosis, and gradually transforms infected B cells into lymphoblastoid cell line (LCL), thus enhancing the ferroptosis resistance of tumor cells [35]. Compared with GC-B cells, lymphoma cells are more competitive and adaptable due to a mutation in BTG1 [144]. Liver cell ferroptosis is caused by an ATF4-dependent elevation of BTG1 in cystine and methionine shortage (CST/Met−) [145]. Compared with hepatocytes or erythrocytes, human B cells have a higher ratio of redox glutathione [146]. Thus, B cells may be susceptible to ferroptosis in this pathway. Moreover, activating transcription factor 4 (ATF4) causes oxidative stress [147], and BTG1 induction is accompanied by the deprivation of glucose and certain amino acids [148]. Given the mechanism related to ferroptosis, BTG1 mutation is likely to enhance the ferroptosis resistance of B lymphoma cells by enhancing cystine or glutamate transport, thus helping B lymphoma cells evade immunity.

16 Benzene-induced anemia of inflammation induces B cell ferroptosis and immunosuppression

In benzene-induced anemia of inflammation, benzene metabolite 1,4-benzoquinone (1,4-BQ) inhibits immunity by stimulating B cell death by activating the typical ferroptosis pathway, the iron regulatory protein 1-dihydroorotic acid dehydrogenase-axis lipoxyphenase 12 (IRP1-DHODH-ALOX12) pathway [149].

17 Different subtypes of B cells have different ferroptosis resistance

B1 cells are a distinct lineage of tissue-resident innate-like B cells that play a key role in the immune response to pathogens, such as Streptococcus pneumoniae [136], and are crucial for barrier immunity. Compared with B2 cells, B1a cells contribute more carbon in high-level glycolysis to the tricarboxylic acid (TCA) cycle and pentose phosphate pathway metabolites. CD36 is expressed prominently on the membrane of B1a cells, which are reliant on exogenous fatty acid absorption [150]. Therefore, B1a cells may be highly susceptible to ferroptosis. A study found that when the GPX4 gene was knocked down, CD36-induced lipid peroxidation occurred on the plasma membrane of B1 and MZ-B cells [151]. However, the activity of Fo B cells was unaffected. Compared with Fo B2 cells, B1 and MZ-B cells expressed higher levels of CD36 and absorbed more lipids. GPX4 deletion also induced lipid peroxidation and ferroptosis in B1 and MZ-B cells, but not in Fo B2 cells. As a result, ferroptosis resistance gradually decreased in B2 cells, MZ-B cells, and B1 cells [151].

Although distinct B cell subsets have varying ferroptosis susceptibility, we infer that ferroptosis plays an inhibitory role in all B cell-related immune responses.

18 Ferroptosis impedes NK cell-mediated immune response

NK cells are an important component of tumor immune surveillance system and can recognize and rapidly combat malignant cells without prior sensitization [152]. Upon activation, NK cells release cytotoxic particles containing perforin and granzyme, which directly lyse tumor cells in a manner similar to activated cytotoxic T cells. NK cells are also potent producers of chemokines and cytokines, such as IFN-γ and TNF-α, and are therefore critical for regulating the adaptive immune response [153–155]. NK cells and NK T cells are crucial components of tumor immune surveillance, which was found to inhibit tumor growth and metastasis by modifying the pancreatic TME [156,157]. NK cell functional defects result in increased tumor incidence and growth rate [158]. However, signals in the TME also cause NK cells to differentiate into regulatory subsets that support tumor progression and inhibit other cytotoxic immune cells [159–161]. All these findings show that NK cells are essential against tumor immunity.

19 Tumor induces NK cell ferroptosis and immunosuppression

A recent study found that tumor-associated NK cells display typical ferroptotic traits, and lipid peroxidation related to oxidative stress inhibits NK cell glucose metabolism, leading to NK cell dysfunction in the TME [37]. In a ferroptotic environment, tumor cells can increase the secretion of PGE2, which has a potent immunosuppressive effect on NK cells [162]. In addition, PGE2 can inhibit the invasion of CDC1 to the tumor site by suppressing the release of the cDC1 chemokines CCL5 and XCL1 by NK cells [163]. Tumor-associated fibroblasts in gastric cancer induces NK cell ferroptosis by enhancing iron output, NK transferrin receptor, and FPN1 and reducing the expression of ferritin components (FTL and FTH), resulting in iron deposition in NK cells and inducing ferroptosis [164].

Despite the few studies on the relationship between ferroptosis and NK cells, the findings suggest that ferroptosis plays an inhibitory role in the immune action of NK cells. Further research is required to determine the exact mechanism.

20 Ferroptosis impedes DC-mediated immune response

DCs, which are specialized antigen-presenting cells, are necessary for activating naive T cells and maintaining T cell-dependent immunity [165]. In a non-homeostasis state, an antigen activates the DCs, which then move toward the T cells for homologous contact. This process allows the T cells to grow in situ and unleash their full effector activity [166]. DCs also have many subtypes, each of which has different functions on various immune cells [167]. Whether they also have different types of ferroptosis resistance must be further studied.

21 Tumor induces DC ferroptosis and immunosuppression

Ferroptosis has been reported in the TME, and high concentrations of 4-hydroxynonaldehyde (4-HNE)-protein adduct in tumor-associated DCs may trigger constitutive X-box binding protein-1 (XBP1) activation and DC dysfunction [168]. Recent studies found that 4-HNE is not only a product of lipid peroxidation but can also cause ferroptosis by promoting lipid peroxidation [169,170] As a by-product of lipid peroxidation, the increase in 4-HNE indicates that DC dysfunction may be related to DC ferroptosis.

Coculture experiments between ferroptotic cancer cells and bone marine-derived dendritic cells (BMDCs) found that early ferroptosis cells promote the phenotypic maturation of BMDCS and activate DCs to trigger vaccine effect [171], which is essentially an antigen-activated immune response and does not enhance DC function. Further research revealed that intermediate and terminal ferroptotic cancer cells become phagocytic by lowering the expression of chemokine Ccr6 and Ccr7 (essential factor for DC transport to lymph nodes [172]), leading to phagocytic dysfunction, suppression of antigen cross-presentation, reduction in antigen-specific T cell [173] (Fig.4), and even DC death, all of which work together to suppress anti-tumor immunity.

Fig.4 Effect of ferroptotic cells on immature and mature DCs. On the right side, the decreased expression of CCR6 and CCR7 in DCs stimulated by ferroptotic cells leads to DC dysfunction (path ①, orange arrow). Increased 4-HNE protein adduct can lead to DC dysfunction through the activation of XBP1 (path ②, green arrow). 4-HNE can induce ferroptosis by some mechanisms (path ③, blue arrow). Increased expression of 12/15-LOX in DC leads to increased intracellular lipid ROS in DCs and causes DCs to undergo ferroptosis (path ④, black arrow). On the left side, BMDC differentiation to DC is induced by ferroptotic cells, resulting in the increased expression of 12/15-LOX in BMDC and increased intracellular lipid ROS, leading to ferroptosis in BMDCs. In addition, the release of LPOs can cause DC ferroptosis (path ⑤, black arrow).

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22 Sepsis induces DC ferroptosis and immunosuppression

Ferroptosis plays an important regulatory role in sepsis and is involved in multiple organ failure [174–176]. In septic kidney injury, the BMDCs in mice differentiate into regulatory DCs, which disrupt Th1 initiation and inhibit IFN-γ release from NK cells, suppressing the innate immune mechanism in the lung against Pseudomonas [177]. In addition, bone marrow-derived naive DCs produce high levels of 12/15-lipoxygenase (LOX). As DCs age, their 12/15-LOX expression gradually decreases [33]. 15-LOX-mediated PE oxidation, particularly those containing AA and adrenaline ethanolamine, is crucial for ferroptosis [178]. Naive DCs might be highly sensitive to ferroptosis. The phospholipid oxidation products derived from 12/15-LOX can inhibit LPS-induced DC maturation and activate the promoter of NRF2-associated antioxidant genes to inhibit DC maturation [33]. Therefore, in a ferroptotic environment, DCs may activate the NRF2 antioxidant pathway in response to the increased expression of 12/15-LOX stimulated by ferroptosis. However, the NRF2-related pathway may inhibit the maturation and differentiation of DCs and the differentiation of T cells induced by DCs, thus rendering the immune system dysfunctional. This finding suggests that ferroptosis contributes to immunosuppression. The NRF2-related pathway protects cells from oxidative stress-induced injury [179]. Further strengthening NRF2 expression can ensure the role of the immune system by clearing the peroxides in the intracellular environment and then ensuring the number of survival DCs to achieve the therapeutic effect. However, the specific mechanism of ferroptosis affecting BMDC differentiation remains to be further explored.

23 Atherosclerosis induces DC ferroptosis and immunosuppression

Atherosclerosis is a typical disease related to ferroptosis. The formation of atherosclerotic plaque is related to ferroptosis in vascular endothelial cells [180–182]. Under certain conditions, endothelial cells can influence surrounding infiltration through secretory bodies [89,183]. DCs are important cells in the deposition of liquid in atherosclerosis, activation of macrophages, and promotion of TH1 immune response [184] on the surface of endothelial cells. After iron overload in endothelial cells, the secreted ferritin exosomes transfer part of iron to DCs, eventually lead to the ferroptosis of DCs thus inhibiting the immune response.

Ferroptosis inhibits the immune response involving DCs regardless of the stage, and the mechanism of ferroptosis on DCs varies at different stages.

24 Ferroptosis impedes MDSC-mediated immune response

MDSCs are defined as a heterogeneous population of immature cells derived from myeloid progenitors with immunosuppressive functions and accumulate in cancer and chronic inflammation, making the disease worse [185–187]. MDSCs directly promote tumor growth and progression by secreting growth promoting mediators and inhibit T and NK cell functions. As a regulator, MDSCs can regulate ROS, Arg-1, and NO for immune surveillance. MDSCs normally inhibit T cell proliferation by secreting iNOS and Arg1 and suppressing B cells by secreting IL-1 [188–190].

25 MDSC helps tumor cells evade T cell immunity

When TNFs bind to the tumor necrosis factor receptor 1 inducing phosphorylated STAT3, myeloid cell precursors undergo normal myeloid precursor proliferation and differentiation into MDSCs [191]. The death ligand encoded by the CD274 gene can hinder the secretion of T cell cytotoxic factors and prevent cancer cells from ferroptosis by binding to PD-1, which is an inhibitory receptor on T cells [110,111]. Myeloid cells are also the primary source of PD-L1 [192]. PD-L1 is expressed by tumor-invasive MDSC subpopulations but not by tumor noninvasive MDSC subpopulations [193]. MDSCs can accumulate in chronically inflamed TMEs [191] (Fig.5). T cell PD-1 can recognize tumor cell PD-L1, indicating that tumor-infiltrating MDSCs compete with tumor cells to bind T cells. Therefore, only a few tumor cells are recognized by T cells and cleared, and most tumor cells achieve immune escape. T cells bound to MDSCs are driven to ferroptosis, and immunity is suppressed (Fig.5). High levels of systemic ${\mathrm{x}}_{\mathrm{c}}^{-}$ and expression can prevent the ferroptosis of tumor-infiltrating MDSCs and affect the stability of p53 protein by TNF-α secreted by CD8⁺ T cells [194]. Neutral ceramidase (N-acylsphingosine amidohydrolase (ASAH2)) is highly expressed in tumor-infiltrating MDSCs in colon carcinoma and acts as an MDSC survival factor. MDSCs expressing high levels of systemic ${\mathrm{x}}_{\mathrm{c}}^{-}$ lead to strong cystine uptake. However, due to the lack of ASC transporters, systemic ${\mathrm{x}}_{\mathrm{c}}^{-}$ cannot transport cysteine. MDSCs can vie for cystine with other immune cells and fail to deliver cystine to the TME, depleting the cyst(e)ine of T cells [195,196], thwarting the immunological response, and allowing tumor cells to escape the immune system.

Fig.5 Mechanism by which MDSC promotes tumor by inhibiting T cells. (A) T cells secrete TNF-α to stimulate the phosphorylation of STAT3 in MDC, which leads to the differentiation of MDCs into MDSCs. Tumor-infiltrating MDSCs can express PD-L1 and cause T cell dysfunction by binding to PD-1 on T cell membrane. (B) Tumor cells and tumor-infiltrating MDSCs express PD-L1 in tumor microenvironment. After T cells are bound by MDSCs, tumor cells can escape the immune system and proliferate rapidly.

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26 Different subtypes of MDSCs have different ferroptosis resistance

MDSCs can be further divided into two populations: monocyte MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). Morphologically, M-MDSCs resemble monocytes, and PMN-MDSCs have a pleomorphic nucleus similar to PMN cells [197–199]. Moreover, PMN-MDSCs are immune-suppressive and can spontaneously die due to ferroptosis in the TME and induce the release of oxidized lipids, thus inhibiting T cell function. Compared with the PMN-MDSCs secreted from bone marrow and spleen, tumor PMN-MDSCs have the lowest ferroptosis resistance [200–202]. Researchers used single-cell RNA sequencing to compare TINs (also called PMN-MDSCs) and circulating neutrophils in mouse breast tumor models and found that aconite decarboxylase 1 (Acod1) is the most significantly upregulated metabolic enzyme in mouse TINs. Furthermore, Acod1 is highly expressed in human TINs. When activated by the GM-CSF-JAK/STAT5-C/EBPb pathway, Acod1 generates econic acid, which facilitates NRF2-dependent resistance to ferroptosis and preserves TIN persistence. In addition, TINs can inhibit the proliferation of CD4⁺ and CD8⁺ T cells and the function of T cells through various mechanisms such as PD-L1 and arginase 1 (Arg1) expression, leading to immunosuppression [36].

27 Lupus nephritis (LN) induces immune cell ferroptosis and immunosuppression through MDSCs

Research has demonstrated a correlation between ferroptosis and renal damage disease. LN causes abnormally activated lipid peroxidation in renal epithelial cells, macrophages [203], and neutrophils [72,73]. It also causes excessive oxidative stress in podocytes, and this damage is specifically brought on by MDSCs’ ROS upregulation [204]. Thus, MDSCs may also govern the aberrant stimulation of lipid peroxidation in neutrophils, renal epithelial cells, and macrophages. Given that the high iNOS expression of MDSCs may strengthen their resistance to ferroptosis, they can enrich themselves in a ferroptotic environment than other immune cells, which would aid in ferroptosis and suppressing immunity.

In summary, MDSCs may have a high resistance to ferroptosis. Owing to their strong immunosuppressive function, MDSC-related inhibition pathway may be a key immunosuppressive pathway in ferroptosis-related diseases.

Fig.6 Timeline of ferroptosis resistance in immune cell research. > means that ferroptosis resistance is greater than.

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28 Discussion

Although ferroptosis has been a favorite in antitumor immunity studies, its interaction with immune cells has been poorly studied. Authors conclude that ferroptosis inhibits the immune response. On the one hand, ferroptosis suppresses the immune response by reducing the number of immune cells. On the other hand, ferroptosis can inhibit immune response by altering the phenotype and activity of immune cells. However, many studies have given the false impression that ferroptosis may activate the immune function. In neutrophil-related immunity, neutrophils can transfer granules containing myeloperoxidase into tumor cells, inducing ferroptosis in tumor cells [205]. Lipocalin 2 (LCN2), secreted by tissue-infiltrating neutrophils, induces ferroptosis in lung cancer malignant stroma through its increased expression in adipose and muscle tissues [206]. This ability may be attributed to the higher resistance of neutrophils to ferroptosis compared with adipose cells and muscle cells. Neutrophils are functionally impaired by ferroptosis but can still survive. When ferroptosis gradually deepens and neutrophils could not bear it, they export overloaded ferroptosis-related proteins to other cells for survival. Meanwhile, the neighboring cells have low ferroptosis resistance and die quickly after receiving ferroptosis-related proteins. Owing to their innate antigen-recognition function, immune cells are the first to sense ferroptosis. In addition, the PMN-released NETs from sepsis-associated acute lung injury induce ferroptosis in alveolar epithelial cells by activating the Toll-like receptor 9/myeloid differentiation factor 88/nuclear transcription factor kappa β (TLR9/MyD88/NF-kβ) pathway, promoting the m⁶A modification of GPX4 mediated by methyltransferase methyltransferase-like 3/YTH domain family protein 2 [207]. Thus, ferroptosis factors may also be involved in the ferroptosis mechanism of the released NETs in this environment.

A contradiction in T cells is that TNF-α can promote the ${\mathrm{x}}_{\mathrm{c}}^{-}$ system of fibroblasts, thereby protecting the cells from ferroptosis [53]. This mechanism may also occur in tumor cells. However, TNF always plays a role in killing tumors because the tumor inhibition mechanism of TNF is the dominant mechanism under pathological conditions. This finding may provide a new direction for anti-tumor immunity.

Given that the mechanism of ferroptosis on NK cells and DCs is less studied, this paper mainly discusses the indirect effect of ferroptosis on the number and function of these two cells to achieve immune suppression. NK cells and DCs are heterogeneous, and different cell subtypes must have different resistance to ferroptosis. This finding is expected to provide a new direction for ferroptosis-related diseases.

The effects of ferroptosis on B cells, T cells, and macrophages are relatively complex. Immunosuppression can be simply divided into three stages. In the first stage, the decrease in immunosuppressive cells is less than that in immune-promoting cells, and the function of the latter is more impaired. In the middle stage, immunosuppressive and immune-promoting cells receive death threats. To protect themselves, they export ferroptosis substances to make surrounding cells die first so they can live for a long period of time. In the late stage, only a few immune cells are left, and only a few cells with strong ferroptosis resistance can be screened out. The overall immune system collapse cannot be saved.

Compared with T cells or B cells that have immunosuppressive subtypes with high ferroptosis resistance, no study has focused on Breg ferroptosis in B cells. However, properties similar to Tregs might be present. For example, Breg is associated with the suppression of excessive inflammation [208]. Breg cells induce T cells to differentiate into Treg cells and maintain the Treg function. Mice containing B cell-specific IL-10 deficiency also exhibit Treg cell deficiency, which is associated with the growth of pro-inflammatory T cells after the induction of autoimmunity [209–211]. Breg cells indirectly inhibit the differentiation of helper T cell 1 (Th1) and Th17 cells by inhibiting the production of pro-inflammatory cytokines by DCs [212,213]. In addition to expressing IL-10, Breg cells express other immunomodulatory cytokines, including TGF-β and IL-35. LPS-activated B cells can induce CD4⁺ T cell apoptosis and CD8⁺ effector T cell energy by producing TGF-β [214,215]. In addition, TGF-β promotes Fe²⁺ accumulation in fibroblasts by upregulating transferrin receptor protein 1 (also known as CD71) [216]. Under certain conditions, fibroblasts secrete exosomes, which may transfer iron to surrounding infiltrating immune cells and thus achieve immunosuppression. These findings may shed new light on ferroptosis-related diseases.

Finally, the immune response of the body is a systematic response, and the changes in one kind of immune cell may not necessarily reflect the changes in the whole immune system. Therefore, in this environment, the sensitivity of all immune cell subtypes to ferroptosis, the sequence of cell death, and the last super resistant immune cell may be new therapeutic targets, and their specific mechanisms must be further studied.

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Acknowledgments

The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (Nos. 82172147, 81571880, 81373147, 30901555, and 30972870), the Natural Science Foundation of Hunan Province (Nos. 2021JJ30900 and 2016JJ2157) and the Graduate Innovation Project of Central South University (No. 2024ZZTS0864).

Compliance with ethics guidelines

Conflict of interests Nina He, Dun Yuan, Minjie Luo, Qing Xu, Zhongchi Wen, Ziqin Wang, Jie Zhao and Ying Liu declare that they have no conflict of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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