Review Article

How Oxidative Stress Modifies the Immune Response Landscape in Cancer

Introduction

Reactive oxidants, or oxidizing agents, are defined as free radicals or unstable atoms/molecules with unpaired electrons, exhibiting a strong tendency to pair these electrons for stability. Due to their high reactivity, they readily accept an electron from electron donors or reducing agents.^1,2 Under normal physiological conditions and homeostasis, non-destructive concentrations of free radicals are tightly regulated by antioxidant agents.³ However, excessive production or uncontrolled accumulation of these reactive species can directly or indirectly damage essential biomolecules, activating molecular and cellular pathways linked to inflammation and carcinogenesis.^3-7 Consequently, reactive oxidants may exert beneficial or harmful effects depending on their concentration.^8,9 Reactive species can originate from endogenous sources, including growth factors, cytokines, metabolic processes, and immune cells,^10,11 or from exogenous factors such as dietary nutrients, UV rays, the microbiome, and environmental xenobiotics. Both endogenous and exogenous sources contribute significantly to oxidative damage of biomolecules (e.g., DNA, lipids, and proteins), ultimately leading to reactive oxygen species (ROS) accumulation, oxidative stress, and potential neoplastic transformation.^3,10,12-14

In biological systems and clinical settings, four primary classes of reactive species are recognized based on their structural composition¹⁵:

simple

• ROS

• Reactive nitrogen species (RNS)

• Reactive sulfur species (RSS)

• Reactive chlorine species (RCS)

Reactive species encompass both radical and non-radical forms.¹⁶ For instance, RNS include radicals like nitric oxide (NO∙) and non-radicals such as peroxynitrite (ONOO−), whereas RCS consist of atomic chlorine (Cl∙) and hypochlorous acid (HOCl) as the non-radical form.^17,18 Among reactive species, nitrogen and oxygen radicals, especially superoxide anions (O2∙−) and ONOO−, are highly reactive and carcinogenic, produced via both endogenous and exogenous pathways that induce oxidative stress, inflammation, and tumor development.^1,17,19-21

Inflammation, the body’s natural response to endogenous and exogenous stimuli, is characterized by the recruitment and infiltration of inflammatory cells into target tissues, aiming to eliminate harmful stimuli, repair damage, and restore tissue homeostasis. This inflammatory response persists until pathogens are eradicated, homeostasis is reestablished, and tissue repair mechanisms are activated.^22,23

Inflammatory responses involve innate and adaptive immunity components, including phagocytes (neutrophils/macrophages), dendritic cells (DCs), mast cells, eosinophils, leukocytes, monocytes, natural killer cells, lymphocytes, and various pro-inflammatory molecules such as cytokines, chemokines, proteases, and reactive nitrogen-oxygen species (RONS).^24-26

During inflammation, antioxidant and cytoprotective mechanisms support redox homeostasis by activating genes involved in tissue repair.²⁷ Unchecked inflammatory responses, however, can cause tissue damage and cellular hyperplasia due to excessive RONS production by inflammatory cells, which disrupts antioxidant pathways,²⁸ leading to oxidative stress.²⁹

Cellular and extracellular redox buffering systems, which consist of key enzymatic antioxidants (e.g., catalase [CAT], superoxide dismutase [SOD], nitric oxide synthases [NOSs], glutathione peroxidase [GPx], and thioredoxin reductase [TR]) and non-enzymatic antioxidants (e.g., ascorbate (vitamin C), β-carotene, α-tocopherol (vitamin E), and flavonoids), play a crucial role in maintaining ROS/RNS at safe levels.^3,30-32 Both enzymatic and non-enzymatic antioxidants work to protect biomolecules by reducing RONS levels. Antioxidants further mitigate inflammation by lowering the levels of nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), cytokines, and nitric oxide, commonly utilized to defend against inflammation and cancer. Conversely, high doses of exogenous antioxidants can be toxic, exerting pro-oxidative, pro-nitrosative, pro-glycation, and pro-inflammatory effects.^33-35 Imbalances in RONS and antioxidant production that disrupt redox signaling can trigger pro-inflammatory signaling pathways, resulting in the oxidation of biomolecules such as proteins, phospholipids, carbohydrates, and nucleic acids, ultimately contributing to cellular degeneration, genomic instability, mutation, and functional decline.^36,37

Inflammatory Conditions: Basic Concepts

Acute Inflammatory Condition

Inflammation is broadly classified into two types: acute and chronic. Each type initiates specific signaling pathways to stimulate both innate and adaptive immune responses.^36,38 Acute inflammation represents the body’s initial response to harmful stimuli, characterized by the activation of innate non-specific immunity. This process is triggered when pathogen-associated molecular patterns (PAMPs) are detected by pattern recognition receptors (PRRs), particularly those in the Toll-like receptor (TLR) family.³⁹ TLR-4, which is specifically activated by lipopolysaccharides (LPS) and other pathogen-related molecules, plays a critical role in activating innate immune responses and inducing acute inflammation and oxidative stress.^22,40 Granulocytes are the predominant inflammatory cells in acute inflammation, mobilized to the site of infection or injury.^41,42 Various innate immune cells, such as DCs, macrophages, neutrophils, fibroblasts, mast cells, and circulating leukocytes, express PRRs to recognize PAMPs and respond to bacterial components like LPS, lipoteichoic acid, or peptidoglycans, leading to acute inflammatory responses.^43-45

The initial acute inflammatory response includes the degranulation of neutrophils and platelets, followed by the activation of tissue macrophages ⁴⁵. In addition, acute inflammation activates DCs, which function as professional antigen-presenting cells (APCs), enabling them to capture and process antigens for presentation to naive T cells. Activated macrophages and DCs subsequently release various inflammatory mediators, including immunoregulatory cytokines, chemokines, anti-inflammatory lipid mediators (such as leukotrienes and prostaglandins), and growth factors. These mediators recruit, differentiate, and activate monocytes and lymphocytes, augmenting both anti-inflammatory and anti-tumor immune responses.⁴⁶

The release of anti-inflammatory factors, including lipid mediators, cytokines, and growth factors, helps terminate excessive inflammation, clear cellular and microbial debris, and initiate tissue repair and regeneration, thus restoring homeostasis. Consequently, acute inflammation plays a crucial immunostimulatory role during its early stages, and complete suppression of this response may impair antitumor immunity. Additionally, these factors prevent the overactivation of potentially damaging adaptive immune cells by stimulating regulatory T and B cells, which in turn modulate prolonged immune responses.⁴⁷

Simultaneously, an oxidative burst associated with phagocytosis occurs, releasing toxic reactive species such as ROS (e.g., superoxide radicals and hydrogen peroxide). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a significant enzyme present in the plasma membrane and vascular system, activates leukocytes and releases reactive species like superoxide anions (O2•−) at the injury site, playing a key role in inflammation-induced peripheral vascular damage.⁴⁸

Chronic Inflammation

Failure of the immune system to control or eliminate pro-inflammatory stimuli during acute inflammation can lead to chronic inflammation, which may result in tissue fibrosis, necrosis, autoimmune diseases, and cancer. Chronic inflammation is primarily characterized by the continuous release of inflammatory factors and persistent tissue damage.^49,50 In this prolonged inflammatory state, macrophages and lymphocytes are the predominant infiltrating cells.^51,52

Chronic inflammation is linked to various diseases, including diabetes, chronic heart failure, atherosclerosis, neurodegenerative diseases, and cancer, either directly or indirectly.^53-56 In chronic inflammatory conditions, excessive ROS/RNS production contributes to oxidative stress and DNA damage, leading to the depletion of cellular antioxidants. The prolonged presence of inflammatory cells induces DNA damage, promoting cell transformation and increasing the mutation frequency.²⁸ Additionally, chronic inflammation, through the continuous release of mediators and RNOS, activates pathways such as NF-κB and cyclooxygenase-2 (COX-2), which can induce mutations in proto-oncogenes and tumor suppressor genes, ultimately suppressing immune responses and promoting cellular malignancy.⁵⁷ Studies have further demonstrated that unresolved long-standing inflammation is associated with increased carcinogenic potential and accelerated tumor progression.^58,59

Relationship Between Oxidative Stress and Inflammation

Studies indicate that oxidative stress plays a pivotal role in the pathophysiology of inflammation.^60,61 Numerous findings highlight the reciprocal relationship between chronic inflammation and oxidative stress, with each process enhancing the other. This mutual interaction creates a self-perpetuating cycle that promotes inflammatory cascades, chronic inflammatory disorders, and an increased risk of cancer.^59,62,63

Chronic inflammation elevates reactive oxygen and nitrogen species (RONS) levels, contributing to oxidative stress. Conversely, oxidative stress, as a core component in chronic inflammation, activates various pro-inflammatory pathways, thereby advancing the pathogenesis of chronic diseases and cancer^19,64. In response to inflammation or tissue damage, various intracellular and extracellular signals are released, which act as damage-associated molecular patterns (DAMPs), alarmins, or danger signals. These molecules initiate inflammatory cascades by engaging PRRs.^65,66

The release of ROS into the extracellular environment can stimulate immune responses.^67,68 Moreover, the oxidative stress state can lead to modifications of biomolecules (e.g., lipids and proteins), resulting in the formation of “structural neo-epitopes”. These neo-epitopes, or oxidation-specific epitopes (OSEs), serve as potent DAMPs recognized by receptors of the innate immune system.^69,70 OSEs are now increasingly acknowledged as key mediators in inflammation and chronic diseases, appearing on oxidatively modified self-proteins, lipids, apoptotic cells, and cell debris, where they bind specific PRRs.^67,69,71-74

Innate immune cells detect OSEs via specific receptors and initiate signaling pathways that activate humoral and cellular components of adaptive immunity to eliminate these modified molecules and prevent further inflammatory effects. However, if not adequately cleared, these OSEs act as DAMPs, potentially causing tissue damage, cell death, inflammation, and advancing lesions.^75-77 During inflammation, an increase in oxygen uptake is accompanied by elevated ROS concentrations, promoting the recruitment and infiltration of mast cells and leukocytes into injury sites and enhancing RONS formation. This process, termed the “respiratory burst”, becomes more pronounced in chronic inflammation, heightening the risk of chronic diseases and cancer.^17,78-82

ROS regulate inflammation by initiating pro-inflammatory signaling cascades and activating cytokines, chemokines, and the NLRP3 inflammasome.^83,84 Notably, mitochondria-derived ROS can activate transcription factors such as NF-κB, signal transducer and activator of transcription 3 (STAT3), activator protein 1 (AP-1), hypoxia-inducible factor-1 alpha (HIF-1α), nuclear factor of activated T cells (NFAT), and NFE2-related factor 2 (Nrf2), all of which mediate cellular stress responses.^19,84,85 These transcription factors are critical in regulating cellular processes and gene expression in response to stimuli, including cytokines, growth factors, stress, inflammation, and infections.⁸⁶

The cytosol can produce reactive species from multiple endogenous and exogenous sources. Cytosolic ROS, especially superoxide and hydroperoxides, are often generated in mitochondria and redoxosomes, from which they diffuse into the nucleoplasm, where they interact with nucleic acids and other nuclear components ⁸⁷. In the cytosol and redoxosomes, pro-inflammatory enzymes such as NADPH-oxidases (NOX), inducible nitric oxide synthase (iNOS), COX2, 5-lipoxygenase (5-LOX), and heme-oxygenase-1 (HO-1) can amplify ROS production.^87,88

Additionally, ROS can induce pro-inflammatory mediators, such as COX2, HIF-1α, and iNOS, which stimulate the expression of inflammatory cytokines (e.g., interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]) and chemokines (e.g., IL-8 or CXCL8), all of which are implicated in the pathogenesis of chronic diseases, oxidative stress-related inflammation, and cancer.^87,88 These mediators can also trigger epigenetic changes in specific miRNA profiles, which are involved in the initiation and progression of inflammation-related tumors.^89,90 Moreover, cytokines and chemokines activate NF-κB and STAT3, both of which play crucial roles in cancer progression.^91-93 Research has demonstrated that ROS-induced COX-2 and NF-κB can increase oncogenic K-Ras levels, linking chronic inflammation to cancer progression.⁹⁴ Mutations in Ras isoforms, especially K-Ras, which occur in approximately 25% of all cancers, promote cell proliferation, tumor growth, and angiogenesis.^95-97 During inflammation, Ras stimulates the expression of various inflammatory mediators, including pro-inflammatory cytokines (e.g., IL-1, IL-6, and IL-11) and the chemokine IL-8.⁹⁸ IL-1, IL-6, and TNF-α promote cancer cell growth and tumorigenesis through ROS generation and DNA damage.^99-102 This persistent inflammatory and oxidative environment establishes a vicious cycle that can damage neighboring healthy epithelial and stromal cells, leading to carcinogenesis over time.^87,103

Inflammation in Cancer

The association between inflammation and cancer risk was first recognized in the late 19th century by Rudolph Virchow.¹⁰⁴ Research has demonstrated that inflammation can either promote cancer progression or inhibit it, depending on the type (acute or chronic), extent (local or systemic), and timing (before or after cancer onset) of the inflammatory response.¹⁰⁵ Acute, or therapeutic, inflammation can induce cancer cell death by activating effective anti-tumor immune responses ^106-108. Conversely, chronic or unresolved inflammation fosters an immunosuppressive environment conducive to tumorigenesis, metastasis, and therapeutic resistance.^109,110 High levels of tumor-infiltrating lymphocytes (TILs) in localized inflammation correlate with improved prognosis due to enhanced anti-tumor immunity.^111,112 In contrast, systemic inflammation often promotes tumor growth, worsens prognosis, and is associated with the progression of various cancers, such as colorectal cancer (CRC).^113-115 TILs, frontline soldiers of the adaptive immune system, are recruited to the tumor microenvironment (TME) to fight against tumor cells.¹¹⁶ Systemic inflammation can support tumor growth and spread by increasing vascular permeability, aiding cancer cell movement through blood and lymph vessels, and enhancing endothelial adhesion in metastatic environments.¹¹⁷ The timing of inflammation affects the occurrence of cancer. Inflammation occurring before cancer onset may promote tumor development, whereas inflammation occurring post-cancer may hinder its progression.¹⁰⁵

The differential effects of inflammation types are primarily due to variations in immune cell activity and molecular interactions. For instance, acute inflammation, stimulated by recombinant cytokines, TLR activators, and chemotherapeutic agents, enhances TIL infiltration, M1 macrophage polarization, and NK cell activity within the TME, subsequently boosting adaptive immunity, inhibiting tumor growth, and improving treatment efficacy.^58,118-120

In contrast, chronic inflammation consistently supports cancer development, regardless of its timing. Cancer-promoting inflammation often results in increased immune cells, such as myeloid-derived suppressor cells (MDSCs),¹²¹ regulatory T cells (Tregs),¹²² tumor-associated fibroblasts, and macrophages.¹²³ These cells inhibit cytotoxic T lymphocyte (CTL) responses, weaken immune surveillance, and enhance immunosuppressive activity within the TME. Chronic inflammation also activates the NF-κB pathway, mainly through elevated TNF-α levels, which supports tumor cell survival and growth.^124-126 TNF-α interacts with TNFR1 and TNFR2 receptors, activating pathways like c-Jun N-terminal kinase (JNK), NF-κB, and caspase cascades in cancer cells, with effects that may vary based on dose and receptor expression.^127-130

Evidence suggests that unresolved chronic inflammation significantly increases the risk of cancer as persistent inflammation contributes to malignancies across various cancer types.^99,131,132 Cancer-related inflammation (CRI) is now regarded as the seventh hallmark of cancer as it links chronic inflammation to cancer via enhanced proliferation and survival signals, facilitating angiogenesis, invasion, and metastasis.^99,133-135 This connection is influenced by two pathways: intrinsic and extrinsic. The intrinsic pathway fosters oncogenic transformation, initiating inflammatory cascades, while the extrinsic pathway, mediated by tumor-infiltrating leukocytes, primarily M2 macrophages, regulates CRI. Both pathways recruit transcription and tumorigenic factors such as NF-κB, STAT3, and HIF-1, crucial for promoting tumor-associated inflammation and suppressing anti-tumor immune responses (Figure 1).^136-138

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Figure 1.

Two Interrelated Pathways linking Inflammation and Cancer. Activation of both paths leads to an increase in cancer cell proliferation, angiogenesis, and metastasis

Figure 1.

Two Interrelated Pathways linking Inflammation and Cancer. Activation of both paths leads to an increase in cancer cell proliferation, angiogenesis, and metastasis

A hallmark of CRI is the infiltration of leukocytes, particularly tumor-associated macrophages (TAMs), from blood vessels into affected tissues via chemotaxis.¹³⁹ This is accompanied by elevated levels of pro-inflammatory cytokines, such as IL-6, IL-1β, NF-κB, and TNF-α, and chemokines like CCL2 and CXCL8. These chemokines promote inflammation and tumorigenesis by creating an inflammatory microenvironment that contributes to cancer development.^140-143 The NF-κB pathway plays a central role in regulating inflammatory responses. Inflammatory cytokines, chemokines, and growth factors promote the production of transcription factors, including STAT3, HIF-1, AP-1, and heat shock factor-1 (HSF1), which can affect cancer-specific microRNA expression.¹⁹ It is widely recognized that reactive species and oxidative stress, as pathophysiological events, can induce chronic diseases and cancer via multiple mechanisms.^19,144 They may drive cancer progression through initiation, promotion, and progression stages, ultimately leading to tumor cell migration or metastasis. Furthermore, chronic inflammation is a primary mediator of cancer induction, influenced strongly by reactive species.⁴⁸

The roles of chronic inflammatory mediators in cancer are complex and sometimes paradoxical.^105,110 While uncontrolled inflammation increases cancer risk by promoting proliferation, angiogenesis, invasion, and metastasis, certain inflammatory mediators, such as lipid messengers (prostaglandins) and polypeptide messengers (cytokines and chemokines), can destroy cancer cells and suppress tumor progression by activating effector and cytotoxic immune cells.^105,110 Therapeutic strategies targeting CRI aim to reduce cancer incidence and progression. CRI-based approaches may help shift the tumor-supporting inflammatory environment toward a tumor-suppressive microenvironment, enhance anti-tumor immune responses, and prevent cancer development.

Oxidative Stress in Cancer

The TME, a complex milieu, comprises diverse types of intracellular and extracellular components, inflammatory agents, and immune cells that collectively influence cancer cell behavior toward increased vascularization and metastasis by creating an immunosuppressive environment.^145,146 The physical conditions and cellular makeup of the TME shape the behavior of cancer cells and modify the immune response landscape.¹⁴⁵ Within the TME, immunosuppressive cells, including type II macrophages (M2), MDSCs, regulatory T cells (Tregs), tumor-infiltrating dendritic cells (TIDCs), and reactive species, proliferate. These components hinder the function of immune effector cells, such as natural killer (NK) cells and cytotoxic CD8 + T cells (CTLs), thereby enabling tumor cells to evade immune surveillance and promoting tumor progression.^147-149 Additionally, tumor cells exhibit elevated levels of ROS. Excessive or prolonged ROS production can lead to tissue destruction, oxidative stress, and potentially higher cancer risk.^82,150

Oxidative stress-induced signaling pathways influence multiple facets of cancer cell behavior, including cell cycle regulation, proliferation, apoptosis, energy metabolism, morphology, adhesion, motility, and angiogenesis.^6,151,152

Cancer cells exhibit altered metabolism to meet their increased energy demands for rapid growth and proliferation.²⁰ To support cellular functions such as signal transduction and gene expression, cancer cells generate more ROS than normal cells.²⁰ Accumulated ROS in mitochondria fosters oxidative stress and tumorigenesis through mitochondrial DNA (mtDNA) mutations and activation of oncogenic signaling pathways.^153,154 Oxidative stress also contributes to the initiation and progression of cancer by inducing chromosomal abnormalities and oncogene activation ¹⁵⁵, further associating with cancer angiogenesis, invasion, and metastasis.^156,157 Extensive research has demonstrated that oxidative stress directly affects various cancer types, including colon,¹⁵⁸ colorectal,¹⁵⁹ hepatocellular,¹⁶⁰ ovarian,¹⁶¹ breast,¹⁶² and brain¹⁶³ cancers.

An overabundance of RONS is critical in regulating cancer stem cells and tumor behavior through direct DNA damage or formation of N-nitroso compounds.¹⁶⁴ Regulation of oxidative stress levels is essential for both cancer progression and anti-cancer immunity. ROS can play dual roles in carcinogenesis, depending on their levels. High ROS levels may promote tumor initiation and progression by inducing genetic mutations, activating oncogenic factors, and inhibiting tumor suppressors, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) and p53, thereby fostering cancer initiation.^161,165 On the one hand, high levels of ROS can initiate tumorigenesis and cancer progression.^166,167 Excessive ROS accumulation also enhances tumor growth by disrupting anti-tumor immune cell function, such as T cells and NK cells, and promoting M2 macrophage polarization within the TME, further supporting tumor progression.^168-171 Conversely, extreme accumulation of ROS can exert anti-oncogenic effects by inhibiting tumor cell proliferation. Excessive ROS can induce cancer cell apoptosis through the activation of endoplasmic reticulum stress-, mitochondrial-, and p53-mediated apoptotic pathways, cell cycle arrest, and the ferroptosis pathway in cancer.^{148,161,172-174}

Inflammation and stress-associated signaling pathways play pivotal roles in the development of cancers.^19,175 It has been demonstrated that endogenous ROS-induced oxidation acts as a physiological secondary messenger in cell signaling and apoptosis and modulates or modifies multiple transduction pathways.^176-178 The MAPK, phosphoinositide-3-kinase- (PI3K-) Akt, Janus kinases/signal transducers, and activators of transcription (JAK/STAT), (ERK/MAPK), Ca signaling, the activator protein (AP-1), Keap1-Nrf2-ARE, and mPTP are intracellular pathways which are regulated by ROS.^178-180

NF-𝜅B, epidermal growth factor (EGF), hypoxia, tumor necrosis factor-α (TNF-α), IL-1, IL-6, TNF-α, and interleukin-1β (IL-1β) have long been considered as pro-inflammatory signaling pathways, and mitochondria-derived ROS induce the upregulation of these stimuli in a concentration-dependent manner.^83,178,181 These pathways play an important role in cancer development.^182,183

ROS-induced intracellular pathways are also partially mediated by MAPKs that are involved in cancer.^179,184 PI3K/AKT and RAS/MEK/ERK (ERK/MAPK) pathways are two major signaling pathways in cancer which enhance tumor cell growth, survival, and metabolism of cancer cells and have been identified as promising therapeutic targets for cancer therapy.^185-188 Inhibiting any of these pathways can prevent cancer progression and improve anti-cancer therapy.^185,187,189

Although many studies have shown that genetic mutations can dysregulate kinase activity and hyperactivate the MAPK pathway during induction and progression of tumorigenesis and promote the growth of tumor cells,^182,190 other studies indicated tumor suppressive activity of this pathway through induction of senescence and ubiquitination and degradation of participated essential proteins in cell cycle and survival.¹⁹¹ Senescence is a stable and terminal state of cell cycle arrest associated with changes in different macromolecules and overproduction of proteins (cytokines, proteases, and growth factors), collectively termed the senescence-associated secretory phenotype (SASP). The entry of cells into senescence by proliferative arrest acts as a barrier against tumorigenesis, which could be a desirable outcome for any anticancer therapy.^192,193 It should be noted that SASP possesses anti-tumorigenic and pro-tumorigenic potential.¹⁹⁴

MAPK/ERK pathway activated by RAS promotes degradation of proteins necessary for both cell migration and progression through the cell cycle.¹⁹¹ However, due to the prominent role of ROS-dependent MAPK signaling in cancer development, blocking this pathway could be effective in reducing cancer growth and increasing the effectiveness of anticancer therapies.¹⁹⁵

It can be concluded that the MAPK/ERK pathway shows both oncogenic/tumor suppressor activities depending on the strength of its activity and protein degradation related to senescence and tissue-specific TME^191,196. It seems that ROS can stimulate, inhibit, or regulate tumorigenesis through monitoring the activation of MAPK pathways in different stages of various cancers; therefore, they can be highly promising therapeutic targets for cancer therapy. ¹⁹⁷

Immune Responses in Inflammation, Oxidative Stress, and Cancer

The responses of the immune system are activated against tumor cells via different processes, including innate/adaptive immune responses.^198,199 The innate immune response with neutrophils, monocytes, and DCs and the adaptive immune response with B and T lymphocytes are orchestrated in tumor response. The first line of immunity against invading cancer or pathogens is the activation of innate immunity.¹⁹⁸ This primary response stops the initial spreading of infection and does not activate adaptive immunity and more specific defense mechanisms.²⁰⁰ In fact, through inflammation, adaptive and innate immune responses tend to eradicate invasion. Unfortunately, these inflammatory responses can be detrimental and probably affect different stages of cancer development.¹⁴³ Results of several studies indicate the favorable role of the inflammatory condition in the growth of tumors.^143,201 It is well accepted that acute inflammation is an inevitable part of the anti-pathogenic response and tissue repair.^202,203 Interaction between host immune responses and cancer cells in solid and hematological cancers is complex and inevitable.^204,205 DCs are professional APCs, the main function of which is to capture antigens and present them to effector memory T cells (T EM cells) and stimulate effective anti-tumor immune responses.²⁰⁶ The substantial roles of NK and lymphocytes in immune surveillance have been proven for a long time. Different mechanisms, such as induction of the production of interferons (INF_S) and other mediators indirectly stimulate durable antitumor immunity.^207,208

Innate Immunity

At the beginning of inflammation, innate immune cells are the first line of the immune defense against inflammation.²⁰⁹ Various biological components such as lymphocytes and macrophages are involved in the initiation and propagation of the inflammation.^51,52 This process is facilitated by the overexpression of cytokines, chemokines, and growth factors. These mentioned cells contribute to the enhancement of defense responses that counteract the inflammation-induced agents.^210,211 The inflammatory process is directly related to neutrophil recruitment and clustering.¹⁸¹ Neutrophils are required for selective IL-1β induction, and accumulation of ROS modulates IL-1β-derived neutrophil clustering. Inflammatory-stimulated neutrophils are among the essential sources of ROS production. During pathogenic infections, neutrophils upregulate IL-1β secretion in a ROS-dependent alternative pathway. IL-1β plays a determinative role in establishing inflammatory responses.^212,213

The main partners of phagocyte cell systems, neutrophils and macrophages, have been identified as the first immunological line of host defense against various invading microorganisms during different infections, CRI, exercise, and phagocytosis of cancer cells.^214,215 Based on the stimulation of effector agents, neutrophils are functionally classified into two N1/N2 subdivisions that exhibit anti/pro-tumorigenic activities. They, directly/indirectly by the production of different mediators such as TNF-a, NO, and H₂O₂ or cytokines such as GM-CSF and IFN-g are involved in immunosuppressive and immune stimulatory responses, respectively.^216,217 Neutrophil cells were considered as the first responders to acute inflammation, whereas monocyte/macrophages were recognized as key cellular components involved in the development of chronic inflammation.^218,219 However, several studies indicated that in chronic inflammation, neutrophils participate in the induction of inflammation and release inflammatory mediators such as cytokines, highlighting the recruitment of monocytes/macrophages in acute inflammatory responses. They exhibit dual roles in the promotion or maintenance of many diseases. The plasticity of macrophages and neutrophils allows them to alter their phenotype and various functions in response to different stimuli and environments.^220-223

Many studies have proved the role of oxidative stress, especially ROS, in the disturbance of functional polarization of macrophages.^224,225 Thus, in this section, we discussed macrophage reprogramming and how ROS drives macrophage polarization.

Macrophages, as innate immune cells, are distributed throughout the body^’s tissues and direct innate and adaptive immune responses by the production of biological/pathological active molecules. Hence, macrophages play crucial roles in maintaining tissue homeostasis or promoting malignancy. Macrophages can be differentiated into various types in different conditions.^226,227 Physiological and pathological processes have a decisive role in macrophage reprogramming. An imbalance of macrophage M1-M2 polarization is often associated with various diseases or inflammatory conditions, including obesity, cancer, and rheumatoid arthritis. In addition to the structural and functional differences between the two macrophage phenotypes, the metabolic axis of macrophages in amino acid arginine metabolism. The ability to generate high levels of pro-inflammatory mediators such as IFN-γ, IL -12, IL-1𝛽, TNF-𝛼, and superoxide anions is a hallmark of classically activated macrophages (M1) that gives them the full capability to kill tumor cells.^228-230 M1 macrophages, by induction of nitric oxide synthase enzyme, produce nitric oxide (NO) that plays a vital role in killing microbial components and tumor cells and eradicating tissue debris or microbial residues that neutrophils have failed to remove. Additionally, NO contributes to the clearance of apoptotic bodies of dead neutrophils. Therefore, M1 macrophages are involved in the initial stages of the inflammation process.^231,232 In contrast, the function of alternatively activated M2 macrophages is distinct from the classical phenotype. M2 macrophages release high levels of anti-inflammatory cytokine mediators, including IL-4, IL-10, and tumor growth factor β1 (TGF-β1). Furthermore, low levels of IL-12 expression induce production by the arginase enzyme. Arginase plays a role in reviving inflamed and demolished extracellular matrix (ECM) by stimulating the production of proline and polyamines. The functionality of macrophages may alter from pro-inflammatory to anti-inflammatory phenotype, which can contribute to healing by removing tissue debris.²³³

Neutrophils are the first line of defense against inflammation, infection, and cancer. They constitute 50%-70% of the total circulating white blood cells in humans. An elevated level of circulating neutrophils may be a prognostic indicator for cancer. The TME releases neutrophils in the bone marrow and bloodstream by secretion of granulocyte colony-stimulating factor (G-CSF).^220,234,235 Neutrophil infiltration is significantly increased during CRI, the seventh hallmark of cancer. The initial phase of inflammation is correlated with local recruitment and the rapid influx of neutrophils into the site of inflammation. They produce pro-inflammatory cytokines/chemokines that make up neutrophil extracellular traps (NETs), which can destroy most types of microbes and affect the pathogenesis of many diseases such as cancer and autoimmune disorders. They use both pro/anti-inflammatory signals to stabilize immune responses.²³⁶ NF- κB activation is stimulated following the identification of PAMPs via TLRs and other PRRs that cause neutrophil production. Accumulation of neutrophils initiating MAPK signal transduction pathways that induce sequential activation of Ras, Raf-1, mitogen/extracellular signal-regulated kinase (MEK), and the extracellularly regulated kinase (ERK) pathways, which result in the generation of pro-inflammatory cytokines, including IL-8 and macrophage inflammatory protein-1a (MIP-1a) that induce pro-cancer factors like TGF-β.^237-240 Neutrophils, as potent leukocytes in host immunity, are considered a vital link between innate and adaptive immune responses. Neutrophils aim to boost the efficacy of monoclonal antibodies-related treatments and increase the cytotoxic activity of cancer therapy methods in cancer patients. The early evidence demonstrated that human neutrophils mediate the production of many new antimicrobial proteins in response to various stimuli and synthesize a high level of ROS via the myeloperoxidase (MPO) and NADPH oxidase enzymes.^241,242 ROS are volatile drivers that act as signaling molecules and cause damage to many biological components of microbes and the host.²⁴³ ROS-related neutrophils regulate both cytokine secretion and apoptosis process, playing an essential role in balancing inflammation.²⁴⁴ Therefore, neutrophils/macrophage-targeting agents offer new approaches for clinical translation.

Tumor-associated macrophages and neutrophils (TAM and TAN) are primary inflammatory cells and potent immunosuppressive components of tumors that promote tumor induction and metastasis.^236,245 In the last decade, the role of neutrophils and macrophages in cancer has been extensively investigated. Several studies showed that the anti/pro-tumoral activities exerted by neutrophils and macrophages are controlled mainly by the tumor niche. In the inflammatory media, particularly the tumor site, severe deficiency of adequate oxygen (hypoxia) by inducing the production of type 1 and type 2 hypoxia-inducible factors (HIFs) and NF-𝜅B affects the polarization, killing potency, secretome, penetration, and adhesion to endothelial cells, which are often administrated by tumor-infiltrated neutrophils and macrophages and support tumor formation, advancement, and other cancer-related processes (metastasis, angiogenesis, etc). Tumor-associated macrophages, via diverse mechanisms, can initiate chronic inflammation and get involved.^246,247

In a tumor environment, macrophages and neutrophils are mainly related to cancer development. Tumor-associated neutrophils (TANs) suppress anti-tumor immune responses by generating a high rate of angiogenic-associated factors such as matrix metallopeptidase-9 (MMP-9), IL-10, vascular endothelial growth factor (VEGF), and reactive oxygen/nitrogen species.^248,249 However, the ROS released by neutrophils can cause DNA damage and mutations,^250,251 which are essential for cancer initiation, cell proliferation, CRI, and immune suppression.²⁵² Compared to healthy cells, higher levels of neutrophil-derived ROS, including superoxide anion and hydrogen peroxide, are found in tumor cells that provoke pro-inflammatory and pro-tumorigenic activities and excite oxidative stress that eventually leads to cancer induction and progression.

In promoting carcinogenesis and tumor progression (Figure 2), there are many functional similarities between neutrophils and macrophages. Interactions between them and other tumor-infiltrated-immune cells are influenced by oxygen-sensing pathways, which may lead to pre-malignancy transformation. Oxygen-sensing pathways can modulate neutrophil function and survival responses. However, the exact mechanisms of neutrophils and other immune cell activities are not yet understood due to their highly plastic nature and multilateral functions in cancer. Thus, there are no unified and valid data on the function of neutrophils and immune cells in all diseases and cancers.

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Figure 2.

Immune Suppressive, Tumor Promotion Activities of TAMs in the Tumor Milieu. TAMs play important roles in tumorigenesis and tumor progression. (a) TAMs, by inducing the production of pro-inflammatory and mutagenic factors, are heavily implicated in cancer-related inflammation. (b) Mediators and enzymes secreted by immune-suppressive TAMs via dysfunction of conventional activity of cytotoxic T cells suppress the anti-tumor immune response, leading to infiltration of regulatory T cells. (c) TAMs, by secretion of angiogenic growth factors, promote the formation of new more permeable tumor vessels and production of tissue remodeling proteases (e.g., MMPs). (d) TAMs, by digestion of ECM components through proteolytic enzymes, particularly matrix metalloproteinase (MMPs), and secretion of invasion-inducing growth factors, facilitate the movement and migration ability of malignant cells to invade surrounding tissues. TAM: tumor-associated macrophages; ROI: reactive oxygen intermediates; RNI: reactive nitrogen intermediates; ECM: extracellular matrix

Figure 2.

Immune Suppressive, Tumor Promotion Activities of TAMs in the Tumor Milieu. TAMs play important roles in tumorigenesis and tumor progression. (a) TAMs, by inducing the production of pro-inflammatory and mutagenic factors, are heavily implicated in cancer-related inflammation. (b) Mediators and enzymes secreted by immune-suppressive TAMs via dysfunction of conventional activity of cytotoxic T cells suppress the anti-tumor immune response, leading to infiltration of regulatory T cells. (c) TAMs, by secretion of angiogenic growth factors, promote the formation of new more permeable tumor vessels and production of tissue remodeling proteases (e.g., MMPs). (d) TAMs, by digestion of ECM components through proteolytic enzymes, particularly matrix metalloproteinase (MMPs), and secretion of invasion-inducing growth factors, facilitate the movement and migration ability of malignant cells to invade surrounding tissues. TAM: tumor-associated macrophages; ROI: reactive oxygen intermediates; RNI: reactive nitrogen intermediates; ECM: extracellular matrix

Adaptive Immunity

Environmental exposures such as inflammation can also influence cancer incidence through several mechanisms.²⁵³ Although the role of inflammation is very prominent in innate immune responses, its importance has been proven in the initiation and development of adaptive immune responses. Components of adaptive immunity, such as lymphocytes, cooperate with innate immune cells and get involved during acute and chronic inflammation via the generation of effector/memory cells and organize the inflammatory responses.²⁵⁴

In local inflammatory and acute-phase responses, non-specific innate immunity may be enough to control an inflammatory disease. Otherwise, in uncontrollable/chronic inflammation, specific immune response (especially DC and T-cell immunity) occurs in specialized lymphoid tissue.^255,256 The lymph nodes and spleen act as a screening system, facilitating the transmission of lymphocytes and antigens through the tissue. The antigen can be loaded by macrophages and DCs in the secondary lymphoid tissue, and the filtered lymphocytes can interact with antigen-bearing DCs or macrophages. Therefore, they differentiate into effector/memory cells to eliminate antigens.^257,258

According to the T cell receptor (TCR) expression, T-cells are divided into two major types: γδ and αβ. Different effector functions of αβ cells are classified into: (1) naïve CD4 + T helper (Th) cells (that coordinate the generation of other effector cells), which mediate tolerance and consist of Th1 cells (that produce IFN-g and IL-12), Th2 cells (that produce IL-4, IL-5, and IL-13), Th17 cells (that produce IL-17A, IL-17F, and IL-22f), T regulatory (Treg) cells, and natural killer T (NKT) cells; and (2) cytotoxic CD8 + cells (CTLs) that mediate clearance and suppressing antigen-specific inflammation, killing tumor-intracellular pathogens, thereby contributing to long-term protection.^259,260 Interestingly, T cells display tumor suppressive and tumor promoting characteristics (beneficial and harmful activities, respectively). There is also evidence that many of the T cell subpopulations, which are found in solid tumors, participate in tumor initiation, progression, and metastasis. Elevated numbers of T cells, specifically activated Th cells and CTLs, are associated with improving the survival rates in different cancers.²⁶¹

There are significant differences between non-T cell-inflamed tumors and T cell-inflamed tumors.²⁶² T cell-inflamed tumors are accompanied by the expression and activation of type I IFN (α, β), and production of particular chemokines that attract T cells, antigen presenting cells, cytotoxic effector molecules, and CD8 + T cells with a dysfunctional phenotype. High expression levels of PD-L1, indoleamine-2, 3-dioxygenase (IDO), and FOXP3 + regulatory T cells (Tregs) can induce IFNs inhibitors. In other words, when CTLs are affected by immunosuppressive mediators in the TME and peripheral blood, they lose their antitumor function. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. However, it seems that the use of immunological adjuvant reverses suppressor activity of T cell exhaustion and accelerates host immunity, which can open up new horizons for improving outcomes in severe inflammatory disorders.²⁶² In contrast, in the non-T cell-inflamed phenotype, the expression of type I IFN, CD8 + T cells, and IFN-inducible inhibitory factors does not occur.^262-265

The Effect of Inflammation and Oxidative Stress on Pro-inflammatory Cytokines

Activation and interaction of various effectors and transcription factors, such as STATS, NF-κB, AP-1, SMAD, cytokines, chemokines, caspases, and so on, with each other and their environment can regulate a broad spectrum of cellular and molecular functions within tumors.²⁶⁶ Pro-inflammatory cytokines and chemokines are small second messenger molecules that are secreted during stress or in the damaged tissues. They synchronize diverse biological activities such as cell differentiation, proliferation, and cancer progression by forming a cytokine network within the TME.^99,267

Regardless of their sources and receptors, they display various roles in the immune and inflammatory milieu to either induce tumoricidal function or promote tumor progression.²⁶⁶ It is evident that cytokines have the susceptibility to modulate the redox status of T cells, based on position, stage, and severity of the disease, skewing T cell differentiation toward Th1, Th2, Th9, Th17, Th22, and Treg subsets and inducing anti-tumor immunity, pro-tumorigenic effects and homeostasis maintenance in various types of cancer²⁶⁸ (Figure 3). In different conditions and environments, cytokines augment T-cell differentiation toward specific cell subtypes by the overexpressing of particular growth factors, thus attenuating differentiation of the other T-cell subpopulation. Differentiation towards the Th1 system leads to the production of pro-inflammatory cytokines such as IL-2, IL-12, INF-γ, and TNFα and T-cell-mediated immune responses (cellular immunity).^269,270 Conversely, differentiating towards the Th2 system develops the generation of anti-inflammatory cytokines, including IL-4, IL-10, IL-13, and antibody-mediated immune responses (humoral immunity).^271,272 However, some of them, such as IL-2 and IL-6, often exhibit pleiotropic properties and act as proliferative factors of immune cells in systemic acute phase responses.^273-275

Close

Figure 3.

Cytokines and Transcription Factors Involved in Differentiation of T Cell Subsets from Naïve T Cells

Figure 3.

Cytokines and Transcription Factors Involved in Differentiation of T Cell Subsets from Naïve T Cells

The uncontrolled inflammatory cascade results from the interaction between oxidative stress and pro-inflammatory cytokines, especially TNF-α and NF-κB, which are two major transcription factors responsible for pro-inflammatory gene expression. Cytokines are involved in both local and systemic cancer-related inflammatory responses via interaction and cross-talk with inflammatory mediators and oxidative stress.²⁷⁶

It seems that cytokines and oxidative stress are considered as major stimuli for the activation of intracellular signal pathways and augmentation of the inflammatory cascade, which lead to local damage, edema, inflammation, epigenetic modulation, and/or cell death.^277-279 The intracellular signaling pathways activated by mentioned performers, in turn, activate inflammatory-related processes such as the expression of protein kinases activated by mitogens (MAPK). Oxidizing agents by releasing superoxide and nitric oxide (oxidants) enhance the expression of nuclear transcription factor-κB, signal transducer activator of transcription-3 (STAT3), and production of primary inflammatory mediators and cytokines, particularly iNOS, TNF-α, IL-1β, IL-8, IL-6, and IL-12 that customarily originate from activated leukocytes and have critical roles in initiation and amplification of inflammatory cascade. In the inflamed environment, infiltrated and circulating leukocytes adhere to the endothelium via adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and induce increased serum levels of stress-associated cytokines and chemokines by attaching to the inflammatory mediators.^280,281

Oxidative stress increases the production of cytokines via various mechanisms, including up-regulation of growth factors, transcription factors such as NF-κB, ECM elements, and AP-1.^282,283 TNF-α and IL-1β synergically participate in strengthening the inflammatory responses. Activated macrophages stimulate TNF-α secretion in tumoral and inflamed parts. TNF-α induces ERK1/2, JNK, p38, and NF-κB gene expression through divergent procedures, which results in signaling cell death and microcirculatory circumstances that occur during stages of inflammation.^284,285 Increased inflammatory cytokines and chemokines, growth factors, cell surface adhesion molecules, prostaglandin synthases, and oxidant synthase are mechanisms mediated by NF-κB overexpression. Numerous studies indicated that during CRI, NF-κB creates genetic alterations (amplification, mutations, or deletions) in cancer cells.^286-288 Additionally, expression of NF-κB is induced via the inflammatory cytokines of TNF-α and IL-1b, as well as TLR-MyD88 pathway, the identifier of pathogen-associated conserved molecular structures (MAMPs or PAMPs). Moreover, NF-κB activation plays a critical role in the hypoxic response, through HIF-1α.^289,290 Several experimental pieces of evidence showed the suppressive activity of oxidative stress on the expression of IFN-g and IL-17A originated from differentiated Th1 cells and Th17, respectively, boosting IL-4 expression in inflammatory-related disorders by inducing ERK1/2 activity. On the contrary, IL-12 and IFN-g signals lead to the amplification of Th1 responses and undermine Th2 development by repressing the IL-4 gene.

Inflammasomes, as a complex of cytosolic molecular platforms and innate immune system receptors of the tissue injury-released exogenous PAMPs, and endogenous danger signals or DAMPs possess an upstream sensor protein of the NOD-like receptor (NLR) family, the adaptor protein ASC, and the downstream effector caspases that induce maturity of inflammatory cytokines such as IL-1β, IL-18, and activation of caspases, particularly caspase-1 in stress status, inflammatory disorders, and oncogenic viral infections.^291,292 Activation of an inflammation-related caspase (caspase-1) triggers the release of pro-inflammatory cytokines and results in a particular type of pro-inflammatory programmed host cell death known as pyroptosis, which is different from apoptosis.²⁹³

Many contradictions are reported regarding the role of the ROS-dependent pathway in the stimulation of forming inflammasome complexes such as NLRP3 inflammasome activation.^63,294 However, several studies described the activator/regulatory role of mitochondrial ROS (mtROS), NADPH oxidase-derived ROS, and other mediators of ROS as key inflammasome activating signals. An elevated level of ROS, by NLRP3 inflammasome stimulators, upregulates the expression of transcriptional factors, including transcription factor NF-κB and AP-1 through MAPKs, which increases the secretion of pro-inflammatory cytokines.^295-297

It was demonstrated that the pattern of the cytokines could be modified by the oxidative microenvironment, which might influence immune pathologies.

In cancer conditions, the way inflammation participates in the protection/destruction of body tissues is an important and challenging issue.

Although oxidative stress is involved in various age-related conditions and is harmful to human health, it can also have benefits as a therapeutic approach and can become toxic to cancer cells.¹² Balancing between pro-oxidants and anti-oxidants should be performed with great sensitivity because their conditions differ in various cancers and chronic inflammatory diseases.²⁹⁸ Understanding these contradictions is very important. Evaluating the communication between oxidative stress, inflammation, and pathogenicity can be a precious tool for discovering targeted preventive, therapeutic, and diagnostic strategies in humans. Identifying and directly assessing the expression levels of stimulatory agents, assessing the amounts of biological damage caused by oxidants and inflammatory agents, and assessing anti-oxidant conditions such as their activities, levels, and capacity promise alternative approaches to describe their critical roles in carcinogenesis and cancer development in clinical samples of cancer patients.

Inflammation and oxidative stress have been proposed as promising and efficient anti-cancer approaches.^90,299,300 Depending on dosage and amounts, ROS may initiate or inhibit apoptosis and skew cellular and molecular pathways toward necrosis by stimulating c-Jun N-terminal kinase (JNK) and caspases. Several studies have already reported that the toxic threshold level of ROS induces cancer cell death by stimulating biological responses in chronic inflammatory states. Autophagy, apoptosis, adaptation, and enhanced drug sensitivity are mechanisms that can be mediated by increased levels of ROS.^301,302

Immunomodulators

As previously stated, oxidative stress with inappropriate activation of the immune cells may exacerbate inflammation and cause many inflammatory and infectious diseases such as cancer. Cancer cells have higher levels of ROS compared to normal cells. Persistent high levels of ROS can result from an imbalance between oxidant production and antioxidant responses.³⁰³ This perturbation is usually associated with changes in ROS-dependent metabolites that contribute to the progression of inflammatory processes and oxidative stress.³⁰⁴ To solve this issue, immunomodulatory drugs are used to modulate or modify immune responses. By stimulating or suppressing the immune system, immunoregulators normalize the production of immune cells to reduce the body’s adverse immune responses. Immunomodulators may be further divided into immunostimulants and immunosuppressants. The mechanisms for various classes of immunomodulatory drugs are different, which are listed in Table 1.^305,306

Discussion

As mentioned above, chronic inflammation and oxidants are considered the leading causes of cancer progression. We concluded that oxidative stress, as a disease-advancing reaction, can be introduced in a multifactorial context as a critical mechanism for inducing different cellular and molecular pathways that are more favorable for disease progression, inflammation, and cancer. From this study, it could be concluded that chronic inflammation and oxidative stress are described as the leading causes of cancer establishment and progression. Undoubtedly, therapeutic approaches can benefit from the neutralization of tumor-induced inflammation, and oxidative stress for the development of suitable anti-inflammatory-related drugs and the prognosis of neoplastic diseases that may improve treatment regimens against cancer progression. Further research is currently being conducted to identify the precise and constitutive mechanism that remains an exciting and challenging topic. Down-regulation of survival of ROS –induced tumor cells, attention to pro-mutagenic signals of tumor cells, and augmentation of anti-tumor immune responses that are mediated by the infiltrating and circulating effector T cells are three essential strategies that prevent cancer/inflammation-associated signals. Understanding the exact mechanisms of redox signaling, as a super-fast communication procedure, and the roles of redox enzymes is of great importance in designing suitable drugs in this field. This information can be used to manage patients with various diseases or create more effective targeted antioxidant therapy approaches for the treatment of oxidative-induced cancer and chronic inflammation.

Conclusion

This review clearly shows the role of ROS in inflammation and cancer development. Therefore, targeting redox-sensitive pathways and transcription factors could provide promising therapeutic approaches for cancer prevention and treatment in the future. Antioxidant therapy may be explored as a treatment option to reduce cancer incidence and progression.^339-341 Antioxidants, as adjuvant, may positively affect cancer treatment outcomes or inhibit the adverse side effects of conventional therapies such as chemotherapy and radiotherapy.^342,343 Achieving these positive results depends on several factors, including the antioxidant dose, synergism, bioavailability of consumed antioxidants, lifestyle, health status of patients, type and stage of cancer, and so on. Therefore, the therapeutic usefulness of antioxidants in the treatment of cancer still has many aspects that need to be investigated in the future.

Authors’ Contribution

Conceptualization: Somayeh Ashrafi.

Data curation: Neda Zahmatkesh.

Formal analysis: Mehdi Mahdavi.

Funding acquisition: Sara Rahimzadeh.

Investigation: Sara Rahimzadeh.

Methodology: Nastaran Hadizadeh.

Project administration: Nastaran Hadizadeh.

Resources: Sara Rahimzadeh.

Software: Nastaran Hadizadeh.

Supervision: Mohammad Abdollahi, Mohammad Hossein Yazdi.

Validation: Nastaran Hadizadeh.

Visualization: Nastaran Hadizadeh.

Writing original draft: Somayeh Ashrafi, Melika Khanzadeh Tehrani.

Writing-review & editing: Sara Rahimzadeh.

Competing Interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interests.

Ethical Approval

This study was approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.DDRI.REC.1401.036).

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