Oxidative stress and inflammation in breast cancer: Mechanistic interactions and clinical implications

Abstract

The development and progression of breast cancer (BC) are influenced by genetic, hormonal, and metabolic factors, as well as by signals within the tumor microenvironment. A review of studies on BC biology and treatment outcomes was undertaken. The studies were experimental, translational, and clinical, and were indexed in PubMed and Web of Science. The focus was on the connection between oxidative and inflammatory markers and clinical endpoints, as well as intervention strategies that modify these pathways. Oxidative stress and inflammation promote tumor growth, metastasis, and immune evasion by driving various biological activations. New data suggest that biomarkers could enhance BC assessment, but strategies are limited. Inflammation and oxidative stress are closely connected processes in BC and may offer important opportunities for therapy. In the future, research should combine molecular studies with clinical trials to improve our understanding of this interaction and determine its clinical value for prognosis and treatment.

Key Words: Breast cancer; Oxidative stress; Inflammation; Tumor microenvironment; Triple-negative breast cancer; Biomarkers

Core Tip: This review integrates contemporary findings regarding the bidirectional interaction between oxidative stress and inflammation in breast cancer, emphasizing common signaling pathways that facilitate tumor initiation, development, and treatment resistance. This work examines how reactive oxygen species alter the tumor microenvironment, drive genetic instability, and sustain inflammation, while inflammatory mediators exacerbate oxidative damage. Furthermore, it assesses novel biomarkers and tailored therapies that leverage this interaction, providing insights into individualized therapeutic approaches and prospective tactics to improve treatment efficacy and address resistance.

INTRODUCTION

Breast cancer (BC) is classified as a type of cancer involving the uncontrolled proliferation of cells in breast tissue. Due to variations in its clinical course, therapeutic response, and molecular and biological heterogeneity, it remains a global health problem. While early detection, diagnosis, and improved treatment programs contribute to a good prognosis and high survival rates, metastases to distant organs such as bone, liver, lungs, and brain reduce treatment effectiveness and increase BC-related deaths. Genetic and hormonal factors, as well as oxidative stress, play a significant role in BC biology. Reactive oxygen species (ROS) promote oxidative stress and chronic inflammation, leading to genomic instability, lipid, protein, and DNA damage, dysregulation of the immune response, and strengthening of signaling that supports tumor development. Understanding this oxidative stress-inflammation interaction is crucial for identifying novel biomarkers underlying BC initiation, progression, metastatic spread, and treatment resistance, and for developing new therapeutic strategies[1].

OXIDATIVE STRESS IN BC: SOURCES AND CELLULAR CONSEQUENCES

BC is still the most common cancer in women worldwide, and it varies greatly in terms of its molecular subtypes, clinical course, and response to treatment[1]. Research is increasingly showing the importance of oxidative stress and inflammation in the onset, metastasis, and resistance to BC treatment. These two interrelated biological processes are key to the pathogenesis of BC and represent promising targets for new diagnostic and therapeutic approaches.

In our literature search the following databases were included: PubMed, Scopus, Web of Science, EMBASE, and Google Scholar. The terms were oxidative stress, ROS, inflammation, cytokines, tumor microenvironment (TME), treatment resistance, and redox signaling. Original studies and meta-analyses were the focus, with recent studies prioritized; conference abstracts, editorials, and case reports were excluded. Selected literature was presented in terms of molecular mechanisms (preclinical) and clinical outcomes.

ROS production and the cellular antioxidant system's ability to neutralize these reactive intermediates are out of balance, which is known as oxidative stress[2]. This imbalance is often seen in BC as a result of both extrinsic (such as environmental exposures and chronic inflammation) and intrinsic (such as oncogene activation and mitochondrial dysfunction) factors[3]. ROS are produced by various cellular processes, including the activity of NADPH oxidase, mitochondrial oxidative phosphorylation, and metabolic reprogramming associated with carcinogenesis. For example, in BC cell lines, an increased tendency to produce ROS was associated with human epidermal growth factor receptor 2 (HER2)/neu phenotypes. This is most likely due to downstream PI3K/AKT signaling, which promotes glycolysis and metabolic stress, and oncogenic activation of HER2. This increased oxidative burden makes HER2-positive BC cells more sensitive to further damage caused by ROS, especially when exposed to pro-oxidant anticancer agents[4].

The effects of elevated ROS levels on BC are complex. Moderate increases in ROS act as secondary messengers, using redox-sensitive signaling pathways to promote cell survival, proliferation, and remodeling. Important transcription factors such as nuclear factor-kappaB (NF-κB) and hypoxia-inducible factor (HIF)-1α, which are involved in proliferation, angiogenesis, and metastasis of tumor cells, may be modulated by ROS[5].

Conversely, high ROS levels can cause oxidative damage to lipids, proteins, and DNA, which can result in genomic instability and the creation of damage-associated molecular patterns (DAMPs), which prolong inflammation[6]. The dual role of ROS in cancer biology is further highlighted by their capacity to stimulate both tumor growth and cell death. While moderate ROS levels aid in invasion, metastasis, and the epithelial-mesenchymal transition (EMT), excessive oxidative stress can cause cancer cells to undergo ferroptosis or apoptosis[7].

In BC, oxidative stress and inflammation are closely related. Tumor growth and immune evasion are sustained by a milieu rich in cytokines, chemokines, and immune cells created by chronic inflammatory processes within the TME[1]. Oxidative stress and inflammation interact in both directions: ROS can trigger inflammatory signaling cascades, and inflammatory cells like neutrophils and macrophages produce ROS as part of their effector functions[8]. This vicious circle is best illustrated by the oxidative stress induced by smoking, which damages lipids, proteins, and nucleic acids due to the high levels of reactive oxygen and reactive nitrogen species present in tobacco smoke. Besides triggering carcinogenesis, the damage also triggers inflammatory reactions that increase ROS production. The onset and progression of cancer are driven by a self-reinforcing loop created by the subsequent chronic inflammation[8].

In the BC TME, ROS comes from several different sources. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), neutrophils, and cancer-associated fibroblasts (CAFs) all contribute to the oxidative environment through their metabolic pathways and secretion profiles. Stem cells affect EMT, control redox homeostasis, and, by interacting with tumor cells, promote metastatic spread. One important regulator of mitochondrial ROS production in BC, for example, is the mitochondrial Lon protease[9].

Increased secretion of inflammatory cytokines such as transforming growth factor (TGF)-β, interleukin (IL)-6, IL-13, and vascular endothelial growth factor (VEGF)-A is due to ROS-mediated activation of the p38 and NF-κB signaling pathways, which is further increased by Lon-mediated upregulation. In addition to promoting angiogenesis and EMT, these cytokines polarize macrophages toward the immunosuppressive M2 phenotype, resulting in a TME favorable for tumor growth and metastasis[10].

EMT is particularly important in relation to oxidative stress and inflammation. Through the reversible cellular process, EMT, epithelial cells lose their polarity and adhesion properties and acquire mesenchymal characteristics, which increase motility and invasiveness. EMT activation is coordinated by master transcription factors such as Snail, Twist, and ZEB, which in turn are regulated by redox-sensitive signaling networks. According to mounting evidence that mitochondrial-derived ROS plays a key role in the induction of EMT, reducing mitochondrial ROS production may reduce EMT and its associated metastatic potential[3].

In addition, ROS and TGF-β, a cytokine involved in inflammation and tumor development, act together to increase the redox imbalance in tumor cells, which in turn promotes the development of EMT[5]. This crosstalk between TGF-β signaling and oxidative stress underscores the complexity of EMT regulation in BC.

In BC cells, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is essential for maintaining redox homeostasis. In response to oxidative stress, Nrf2 controls the expression of antioxidant genes. Notably, the gene expression signature based on Nrf2-regulated genes has been shown to improve prognostic stratification of hormone receptor-positive breast carcinoma. In metastatic BC cell lines and tumors, Nrf2 was shown to be constitutively activated in a subset of antioxidant genes that protect against ROS-induced damage. Depletion of Nrf2 results in elevated basal ROS levels and impairs both primary tumor formation and metastatic spread in experimental models[11]. However, because Nrf2 can restore redox homeostasis in cancer stem cells (CSCs), chronic activation can paradoxically support survival and drug resistance, highlighting the effects of context-dependent activation[12].

The relationship between oxidative stress, inflammation, and therapeutic resistance is increasingly recognized as a major barrier to BC treatment. Targeting inflammatory processes or EMT signaling is therefore a promising strategy to overcome multifactorial drug resistance in BC. TAMs, MDSCs, and CAFs secrete inflammatory mediators that create an environment that nurtures CSCs, induces EMT, and upregulates multidrug resistance genes. Promoters of ATP-binding cassette transporter genes - key mediators of drug efflux - contain binding sites for canonical EMT transcription factors like ZEB, Twist, and Snail[13]. Table 1[5-13] provides a comprehensive summary of sources of ROS in BC.

Table 1 Major sources of reactive oxygen species in breast cancer and their cellular consequences.

Source of ROS	Main mechanism	Key downstream effects	Representative pathways/markers
NADPH oxidases (NOX family)	Activation by oncogenic and inflammatory signals in tumor and stromal cells	Increased superoxide production, lipid and protein oxidation, promotion of proliferation and migration	NF-κB, MAPK, PI3K/AKT, MDA, protein carbonyls
Mitochondrial electron transport chain	Electron leakage under hypoxia and high metabolic demand	Mitochondrial ROS accumulation, mtDNA damage, genomic instability, induction of EMT	HIF-1α, DAMPs, 8-OHdG
Oncogene-driven metabolic reprogramming	Warburg effect, enhanced glycolysis, and altered TCA cycle	Elevated basal ROS, redox-sensitive signaling, adaptation of cancer stem cells, therapy resistance	PI3K/AKT, HER2, Nrf2-regulated antioxidant genes
Chronic inflammation	Activation of immune cells (macrophages, neutrophils) and cytokine signaling	Sustained ROS and RNS generation, macromolecular damage, self-perpetuating inflammatory loop	TNF-α, IL-6, COX-2, CXCL8/IL-8
Environmental and lifestyle factors	Smoking, radiation, pollutants, dietary factors	Direct oxidative damage to DNA, lipids and proteins, initiation and promotion of carcinogenesis	8-OHdG, MDA, nitrotyrosine, myeloperoxidase
Anticancer therapies (radio/chemotherapy)	ROS generation as part of cytotoxic mechanism	Tumor cell killing at high ROS, but also selection of resistant clones and long-term tissue/vascular damage	Doxorubicin-induced ROS, radiotherapy-induced oxidative biomarkers

8-OHdG: 8-Hydroxy-2′-deoxyguanosine; ROS: Reactive oxygen species; DAMP: Damage-associated molecular pattern; Nrf2: Nuclear factor erythroid 2-releated factor 2; TNF-α: Tumor necrosis factor-α; IL: Interleukin; TCA: Tricarboxylic acid cycle; RNS: Reactive nitrogen species; MDA: Malondialdehyde; EMT: Epithelial-mesenchymal transition.

INFLAMMATORY PATHWAYS AND THEIR CROSSTALK WITH OXIDATIVE STRESS

BC initiation, promotion, and metastasis are significantly aided by chronic inflammation. The overexpression of growth factors, chemokines, and cytokines that promote tumor growth is facilitated by inflammatory processes[14].

Inflammation is both a cause and an effect of oxidative stress in the TME, defined by the dynamic interactions between immune cells, stromal elements, and tumor cells. NF-κB is one of the key mediators of the association between inflammation and redox changes in BC. NF-κB modulates cellular redox homeostasis by controlling the expression of genes related to prostaglandin synthesis, glutathione (GSH) metabolism, cyclooxygenase (COX), and cytochrome P450 activity. NF-κB is involved in maintaining oxidative stress conditions that are favorable to genomic instability, as evidenced by the different oxidative state changes that occur when it is blocked in different subtypes of BC[15]. Additionally, NF-κB activation is closely linked to persistent low-grade inflammation in tumors, which is frequently brought on by hypoxic environments that also activate HIF-1[6]. Both cyclic and chronic hypoxia increase the production of ROS and reactive nitrogen species, which in turn trigger the HIF-1 and NF-κB signaling pathways, thereby increasing the expression of angiogenic factors such as VEGF-A, chemokines such as CXCL8/IL-8, and pro-inflammatory mediators such as COX-2[16].

TME: MACROPHAGE POLARIZATION AND FIBROBLAST ACTIVATION

TME is formed by recruitment and functional polarization of immune cells, in particular macrophages. TAMs may develop either the proinflammatory phenotype M1 or the anti-inflammatory phenotype M2 depending on local stimuli. Chronic inflammation initially promotes M1 polarization, but M2 polarization takes over as the tumor grows, supporting immune suppression, metastasis, and tumor growth. This phenotypic change is further mediated by hypoxia in the TME via HIF signaling[17].

ROS are required for macrophage polarization. Although some ROS are required for proper polarization of M2 macrophages, M2 macrophages have lower levels of ROS than M1 macrophages due to the expression of more antioxidant enzymes. Inhibition of ROS-generating enzymes or treatment with superoxide dismutase (SOD) mimetics may reduce the expression of M2 markers and the tumor-promoting effect of macrophages[18].

TME fibroblasts also respond to oxidative stimuli. Extracellular SOD (EcSOD), a secreted antioxidant enzyme, is often silenced by methylation of promoters in BC. By scavenging extracellular ROS and interfering with paracrine signaling between fibroblasts and tumor cells, restoring EcSOD expression prevents activation of the c-Met pathway, which is essential for tumor cell invasion[19].

Autophagy is a highly conserved cellular survival mechanism whereby cells break down damaged, misfolded and/or unwanted proteins in lysosomes to maintain cellular health and energy homeostasis. In cancer, autophagy suppresses early tumor formation by limiting oxidative damage, mitochondrial dysfunction, and genomic instability through the elimination of damaged organelles and proteins. After tumor formation, autophagy supports tumor cell survival, depending on tumor type, stage, and genetic characteristics, by recycling cellular substrates that maintain cellular homeostasis. Oxidative stress in BC development is closely linked to autophagy. Elevated ROS levels can activate autophagy as an antioxidant response via redox-sensitive pathways involving AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Nrf2, and mitophagy, and the removal of damaged mitochondria via mitophagy limits ROS production. Autophagy can also modulate inflammation by regulating NF-κB signaling and the release of pro-inflammatory cytokines. Therefore, impaired autophagy can promote persistent ROS accumulation and chronic inflammation, while excessive or treatment-induced autophagy can support tumor cell survival and treatment resistance.

In addition, autophagy has been shown to inhibit isoprenaline-induced M2 polarization via ROS, ERK, and mTOR signaling pathways; inducing autophagy reduces intracellular ROS production and downregulates M2-related molecules[20]. Table 2[17-20] shows TME components involved in oxidative stress and inflammation in BC.

Table 2 Tumor microenvironment components involved in oxidative stress and inflammation in breast cancer.

Cell type/component	ROS/redox features	Inflammatory mediators (examples)	Net effect on tumor biology
M1 TAMs	Higher ROS levels, pro-oxidant phenotype	TNF-α, IL-12, reactive nitrogen species	Anti-tumor immunity, tumor cell killing, but also tissue damage in chronic settings
M2 TAMs	Lower ROS due to increased antioxidant enzymes; redox state supports survival	IL-10, TGF-β, CCL2	Immune suppression, promotion of angiogenesis, EMT and metastasis
MDSCs	ROS production combined with arginase and nitric oxide synthase activity	IL-10, TGF-β	T-cell dysfunction, immune evasion, support of metastatic spread
Neutrophils (N1/N2)	Burst ROS production, neutrophil extracellular traps; phenotype shaped by local redox and cytokine milieu	CXCL1, CXCL8/IL-8, TNF-α	Both pro-tumor and anti-tumor roles can promote angiogenesis and metastasis when chronic
Cancer-associated fibroblasts (CAFs)	Altered antioxidant enzymes; EcSOD silencing increases extracellular ROS	TGF-β, growth factors (HGF), matrix-remodeling molecules	ECM remodeling, stiff stroma, immune exclusion, enhanced invasion and drug resistance
Endothelial cells	ROS-mediated endothelial dysfunction under hypoxia and inflammation	VEGF-A, adhesion molecules, chemokines	Pathological angiogenesis, abnormal vasculature, impaired drug delivery
Cancer stem cells	Controlled ROS at low-to-moderate levels, strong Nrf2-driven antioxidant capacity	Variable interaction with TAMs and CAFs via cytokines and exosomes	Maintenance of stemness, resistance to chemo/radiotherapy, relapse and metastasis

TAM: Tumor-associated macrophage; MDSC: Myeloid-derived suppressor cell; EMT: Epithelial-mesenchymal transition; ECM: Extracellular matrix; ROS: Reactive oxygen species; EcSOD: Extracellular superoxide dismutase; HGF: Hepatocyte growth factor; TNF-α: Tumor necrosis factor-α; IL: Interleukin; Nrf2: Nuclear factor erythroid 2-releated factor 2.

INTERPLAY BETWEEN OXIDATIVE STRESS, INFLAMMATION, AND CELL DEATH PATHWAYS

ROS controls different types of cell death in addition to promoting tumorigenesis. Whether cells undergo necroptosis, ferroptosis (an iron-dependent type of cell death marked by lipid peroxidation), or apoptosis depends on the type and amount of ROS[21]. Through the ZFAND5/SLC3A2 signaling axis, acidosis within the TME can cause ferroptosis in BC by increasing total and lipid ROS levels while depleting GSH (Figure 1). Short-term acidosis also promotes M1 macrophage polarization, suggesting a dual anti-tumor effect through both direct cancer cell killing and immune modulation[22].

Figure 1 Interplay among oxidative stress, inflammation, and regulated cell death pathways in breast cancer. The left panel illustrates major sources of reactive oxygen species (ROS), including mitochondrial dysfunction, NADPH oxidase 2 (NOX2) activation, endoplasmic reticulum stress, radiation, chemotherapy, and hypoxia. Accumulation of ROS, such as superoxide, hydrogen peroxide, hydroxyl radicals, and peroxynitrite, promotes DNA damage, lipid peroxidation, and protein oxidation. These effects are counteracted by antioxidant defense systems, including superoxide dismutase, catalase, glutathione (GSH) peroxidase, and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated transcriptional responses. The right panel summarizes inflammatory stimuli, including infection, damage-associated molecular patterns, tumor cell death, hypoxia, and anticancer therapy, which activate macrophages, neutrophils, and T cells. These immune cells release inflammatory mediators such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, cyclooxygenase-2, and inducible nitric oxide synthase (iNOS), thereby enhancing ROS generation, angiogenesis, invasion, metastasis, and suppression of antitumor immunity. The central panel shows the microenvironment of breast cancer (BC), composed of tumor cells, M1 and M2 macrophages, neutrophils, T cells, cancer-associated fibroblasts, and endothelial cells, highlighting their dynamic interactions with oxidative stress and inflammatory signaling. In the BC microenvironment, oxidative and inflammatory signals converge on redox-sensitive pathways, particularly nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and Nrf2, which regulate tumor-cell proliferation, survival, immune evasion, angiogenesis, and therapeutic resistance. ROS can activate NF-κB and STAT3, increasing the production of inflammatory cytokines, whereas cytokines and inflammatory enzymes stimulate additional ROS production through pathways involving NOX2 and iNOS. This reciprocal interaction establishes a self-amplifying feedback loop that sustains chronic inflammation and oxidative stress. Depending on the intensity, duration, and cellular context of these signals, different regulated cell death pathways may be activated. Apoptosis is mediated through death-receptor and mitochondrial pathways involving caspase-9, caspase-3/7, and Bcl-2 family proteins. Ferroptosis results from iron-dependent lipid ROS accumulation and is regulated by the system Xc-GSH-GPX4 antioxidant axis. Necroptosis is mediated by RIPK1, RIPK3, and phosphorylated MLKL, leading to membrane rupture and the release of inflammatory intracellular contents. Although activation of these pathways may eliminate tumor cells, cancer cells can adapt by increasing antioxidant defenses, altering death-signaling proteins, and activating survival pathways, thereby promoting treatment resistance. Collectively, the crosstalk among oxidative stress, inflammation, and cell death contributes to genomic instability, tumor progression, metastasis, biomarker alterations, and variable therapeutic responses, while also providing potential targets for antioxidant, anti-inflammatory, ferroptosis-inducing, and immunomodulatory strategies. ROS: Reactive oxygen species; NADPH: Nicotinamide adenine dinucleotide phosphate; ER: Endoplasmic reticulum; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; Nrf2: Nuclear factor erythroid 2-related factor 2; M1: Classically activated pro-inflammatory macrophage phenotype; M2: Alternatively activated anti-inflammatory macrophage phenotype; DAMPs: Damage-associated molecular patterns; TNF-α: Tumor necrosis factor-α; IL: Interleukin; COX-2: Cyclooxygenase-2; iNOS: Inducible nitric oxide synthase; NOX2: NADPH oxidase 2; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; Fas: Fas cell surface death receptor; TNFR: Tumor necrosis factor receptor; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma-extra large; Bax: BCL2-associated X protein; Bak: BCL2 antagonist/killer 1; Fe²⁺: Ferrous iron; System Xc-: Cystine/glutamate antiporter system Xc-; SLC7A11: Solute carrier family 7 member 11; GSH: Glutathione; GPX4: Glutathione peroxidase 4; RIPK1: Receptor-interacting serine/threonine-protein kinase 1; RIPK3: Receptor-interacting serine/threonine-protein kinase 3; MLKL: Mixed lineage kinase domain-like pseudokinase. This figure was created by BioRender.com (Supplementary material).

This shows that TME involves complex feedback loops between oxidative stress, inflammatory signals, autophagy, and immune cell function. In triple negative BC (TNBC) cells, inhibition of autophagy increases intracellular ROS, which in turn increases the secretion of macrophage migration inhibitory factor. This cytokine modulates the proliferation of neighboring tumor cells and promotes the polarization of M1 macrophages[23].

NEUTROPHILS AND OTHER IMMUNE CELLS: ADDITIONAL LAYERS OF COMPLEXITY

There is growing recognition of the role neutrophils play in the TME of BC. Chemokines like CXCL1 and CXCL8 mediate their recruitment; once present, they contribute to both pro-tumorigenic and anti-tumorigenic processes through cytokine secretion and ROS production. Neutrophil activity is regulated by critical inflammatory pathways like NF-κB, JAK/STAT, MAPK, and PI3K/AKT. By altering neutrophil survival and chemotactic responses, dysregulation of these pathways can promote angiogenesis, immune suppression, and metastasis[24].

THERAPEUTIC IMPLICATIONS: TARGETING REDOX BALANCE AND INFLAMMATORY SIGNALING

Due to the importance of oxidative stress and inflammation in the pathophysiology of BC, therapeutic approaches aimed at restoring redox homeostasis or altering inflammatory pathways are currently being explored. The Nrf2 pathway, a major regulator of antioxidant responses, stimulates the production of antioxidant molecules such as heme oxygenase-1, which may block important inflammatory pathways such as NF-κB. However, both autophagy and Nrf2 signaling decline with age, making people more susceptible to age-related diseases such as BC[25].

In addition, nanotechnology-based methods are being explored. For example, hydrogen and oxygen nano-bubbles were shown to reduce intracellular ROS production and suppress important inflammatory proteins in MDA-MB-231 BC cells, suggesting that they may be useful in regulating oxidative stress and inflammation for therapeutic benefit[26]. Similarly, fullerene C60 nanoparticles reduce inflammation in cardiac tissue by reducing COX-2 and tumor necrosis factor-α expression and increasing the activity of antioxidant enzymes in animal models of cardiac damage associated with BC[27]. Another novel approach is the use of ROS-responsive prodrugs. At elevated ROS levels, modified peroxamide-based doxorubicin prodrugs show increased cytotoxicity against BC cells while sparing normal cells; treatments that increase intracellular ROS or X-ray irradiation further boost their efficacy[28].

MICRORNAS: REGULATORS AT THE INTERSECTION OF OXIDATIVE STRESS AND INFLAMMATION

In BC, microRNAs (miRNAs) are becoming significant regulators at the interface between oxidative stress and inflammation. ROS can alter miRNA expression profiles that affect cell survival, proliferation, apoptosis, and inflammatory reactions[29]. On the other hand, certain miRNAs control genes related to redox homeostasis. Depending on their targets within these interrelated pathways, miRNAs function as both tumor promoters and suppressors in the progression of BC[1].

CLINICAL IMPLICATIONS OF OXIDATIVE AND INFLAMMATORY BIOMARKERS

Oxidative stress results from an imbalance between the production of ROS and the ability of endogenous antioxidant systems to neutralize these reactive intermediates. Examples of ROS are superoxide anions, hydrogen peroxide, and hydroxyl radicals, which are produced as by-products of cellular metabolism and are necessary for cell signaling and homeostasis. However, excessive ROS production or weakened antioxidant defenses may lead to oxidative damage to DNA, proteins, and lipids, which may contribute to tumor growth and spread[30].

Inflammation is another hallmark of cancer, characterized by the release of pro-inflammatory cytokines and the activation of immune cells. Chronic inflammation may promote the development, growth, and metastasis of tumors by various mechanisms, including induction of genomic instability, stimulation of angiogenesis, and suppression of antitumor immunity. As oxidative stress and inflammation are closely related to the pathophysiology of BC, their cyclic relationship provides a prime example of how environmental exposure can induce a vicious cycle, whereby oxidative stress damages macromolecules and triggers inflammatory pathways, which in turn increase ROS production and prolong tissue damage[8].

Oxidative and inflammatory biomarkers in BC have different clinical implications. The biomarkers used to indicate oxidative stress are products of lipid peroxidation (e.g., malondialdehyde), oxidation of proteins (e.g., carbonyl-protein), oxidation of DNA (e.g., 8-hydroxyguanosine), and the activity of antioxidant enzymes. Longitudinal studies have shown a correlation between oxidative stress serum biomarkers (e.g., in BC survivors treated with radiation: 8-hydroxyguanosine, myeloperoxidase) and post-treatment exhaustion. These results highlight the potential for oxidative stress indicators to be used both for long-term survival and for monitoring treatment-related toxicity[31].

The intrinsic antioxidant properties of high-density lipoprotein (HDL) particles may influence the course of BC. It was shown that women with TNBC had higher HDL antioxidant activity than healthy controls, irrespective of plasma HDL cholesterol. In particular, HDL in TNBC patients demonstrated a 22% greater ability to delay the oxidation of low-density lipoproteins, a process positively correlated to the apolipoprotein A-I content of HDL. This increased antioxidant activity was more pronounced in advanced TNBC, suggesting a compensatory response to increased oxidative stress in the tumor environment[32].

The interaction of oxidative stress, inflammation, and insulin resistance also influences BC risk. Higher triglyceride-glucose index, a surrogate marker for insulin resistance, was linked to higher odds of prevalent BC in a large cohort study involving perimenopausal and postmenopausal women. The ratio of uric acid to HDL cholesterol, a marker of oxidative stress, and the neutrophil-to-platelet ratio, a marker of inflammation, both served to explain the relationship in a mediation analysis. These results show a correlation between oxidative stress, inflammation, and metabolic dysfunction and BC risk[33].

On a molecular level, oncogenic miRNAs such as miR-526b and miR-655 are associated with aggressive BC characteristics by modulating oxidative stress pathways. Overexpression of these miRNAs increases ROS levels via the signaling axes COX-2, EP4, and PI3K, while also conferring resistance to oxidative damage through alterations in DNA repair mechanisms and p53 signaling. Through transcriptomic studies, key genes associated with redox homeostasis, such as OAS2, and genes associated with immune regulation have been identified. Data from these studies suggest that some miRNAs may be both biomarkers and therapeutic targets for regulating the oxidative stress response in BC. Furthermore, observable alterations in metabolic signaling pathways may be downstream effects of miRNAs that induce transcriptional reprogramming[34].

Through mechanisms related to oxidative stress, the secretome, a family of proteins secreted by cancer cells, also helps to regulate TME. YWHAB, SFN, TXNDC12, and MYL6B-proteins related to apoptosis, oxidative stress response, membrane transport, and motility-were found to be upregulated in miR-526b and miR-655-expressing BC cells. It is noteworthy that SFN and YWHAB have been confirmed as potential blood biomarkers for the differentiation of early- and late-stage BC[35].

Infiltrating immune cells are exposed to severe metabolic challenges due to TME. Hypoxia, oxidative stress, and metabolic alterations within the TME contribute to immunosuppression and impair T-lymphocyte effector function, thereby promoting resistance to immune checkpoint inhibitors[36].

Ferroptosis, a type of iron-dependent cell death characterized by lipid peroxidation, has been identified as a particular vulnerability of TNBC. Compared to other BC subtypes, TNBC cells have a unique metabolic profile associated with iron and GSH metabolism, which predisposes them to ferroptosis. Induction of ferroptosis not only reduces the viability of TNBC cells but also changes the TME by releasing damage-related molecular patterns that attract immune cells to the tumor site. Important ferroptosis-related genes such as GPX4 and ACSL4 show altered patterns of expression in TNBC tissues and may be used as biomarkers for prognosis or diagnosis[37].

The relationship between necroptosis (a regulated form of necrotizing cell death) and long non-coding RNAs (lncRNAs) was also investigated in TNBC. Necroptosis-related genes and associated lncRNAs were used to construct risk models that could predict prognosis and response to immunotherapy. Patients classified as high risk based on these models had decreased infiltration of immune cells and reduced expression of immune checkpoint molecules, which are associated with a poor response to immunotherapy[38].

Therapeutic approaches that target oxidative stress pathways are still being researched. For instance, iron oxide-based nanocomposites with enzyme-mimic activity have been developed for dual-modality imaging-guided phototherapy; these nanocomposites induce hyperthermia and oxidative stress within tumors while repolarizing TAMs from an immunosuppressive M2 phenotype to a tumoricidal M1 phenotype. Similarly, adapalene, a third-generation retinoid, has demonstrated anti-tumor activity in TNBC models[39]. Table 3[30-39] shows oxidative and inflammatory biomarkers in BC and their clinical implications.

Table 3 Selected oxidative and inflammatory biomarkers in breast cancer and their clinical implications.

Biomarker/signature	Biological process	Clinical association (examples)
Malondialdehyde	Lipid peroxidation	Higher levels associated with increased oxidative stress and more advanced disease
8-hydroxyguanosine	DNA oxidation	Linked to genomic instability and radiotherapy-related toxicity and fatigue
Protein carbonyls	Irreversible protein oxidation	Reflect cumulative oxidative damage, associated with poor prognosis in some cohorts
Antioxidant enzymes (SOD, GPx, CAT)	Endogenous antioxidant defense	Altered activity correlates with tumor stage and treatment response
Myeloperoxidase	Neutrophil-derived oxidant production	Elevated levels related to chronic inflammation and post-treatment fatigue
HDL antioxidant activity	Lipoprotein-associated antioxidant capacity	Increased activity in TNBC as compensatory response to high oxidative stress
Triglyceride-glucose (TyG) index	Insulin resistance, metabolic dysfunction	Higher TyG associated with increased BC risk via oxidative/inflammatory pathways
UHR/NPR	Systemic oxidative stress and inflammation	Related to risk and prognosis; may help refine risk stratification
Ferroptosis-related genes (GPX4, ACSL4)	Iron-dependent lipid peroxidation	Expression patterns associated with TNBC prognosis and potential response to ferroptosis-inducing therapy
Necroptosis-related lncRNA signatures	Regulated necrotic cell death	Risk models predict survival and response to immunotherapy in TNBC

BC: Breast cancer; TNBC: Triple-negative breast cancer; HDL: High-density lipoprotein; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; CAT: Catalase; NPR: Neutrophil-to-platelet ratio; UHR: Uric acid-to-HDL ratio.

TRANSLATIONAL BARRIERS AND LIMITATIONS

Another characteristic of cancer is inflammation, which is combined with oxidative stress to alter TME. Chronic inflammation of breast tissue may create a pro-tumor environment by releasing cytokines, chemokines, and growth factors that promote angiogenesis, immunosuppression, and extracellular matrix remodeling. Immune cell dysfunction is exacerbated by hypoxia, oxidative stress, and metabolic changes in the TME, which also increase resistance to immunotherapies such as immune checkpoint inhibitors[36]. Genes involved in glycolysis, angiogenesis, and immune evasion are upregulated when the HIFs commonly found in solid tumors such as TNBC are stabilized. For example, hypoxia-induced expression of Annexin A6 in TNBC cells has been shown to increase resistance to EGFR and AR antagonists[40].

The successful clinical application of therapies targeting oxidative stress and inflammation in BC is hampered by several translational barriers, despite notable advancements in our understanding of the molecular underpinnings of these pathways. One major obstacle is the diversity of BC subtypes and their distinct metabolic profiles. TNBC cells exhibit elevated glycolytic activity and glucose uptake, a phenomenon called the Warburg effect, which promotes rapid proliferation and generates excessive ROS as metabolic byproducts. Attempts to overcome this resistance by focusing on glucose metabolism with inhibitors such as metformin or 2-deoxy-D-glucose have shown promise in preclinical models; however, they encounter difficulties with toxicity, selectivity, and compensatory metabolism[41].

The TME itself presents additional barriers to the successful translation of treatments targeting inflammation and oxidative stress. For example, CAFs are required to change the extracellular matrix and create an immunosuppressive niche that prevents the infiltration of immune cells and the passage of drugs. CAF-derived proteins such as SPARC, which have been identified as independent prognostic indicators of poor outcome in TNBC, promote tumor cell migration and invasion while inhibiting adhesion[42].

The thickened stroma produced by the CAF helps to maintain the chronic inflammation within the tumor and acts as a physical barrier to the therapeutic effect of the drug. Creative nanomedicine techniques have attempted to overcome these barriers by creating drug delivery systems that can penetrate the stroma and change CAF activity. For example, liposomes based on ginsenoside Rg3 increased tumor accumulation by glucose transporter-mediated uptake. They suppressed TGF-β signaling, thereby restoring activated CAFs to baseline and increasing drug uptake and anti-tumor activity in TNBC[43].

Emerging diagnostic technologies offer new opportunities to monitor therapeutic responses to inflammation and oxidative stress. Compared to traditional imaging methods, label-free metabolic imaging, which can detect changes in NAD(P)H and FAD by autofluorescence, have demonstrated greater sensitivity in the monitoring of the response to immunotherapy. These techniques allow for real-time visualization of dynamic metabolic changes in tumor cells and immune infiltrates after therapies such as CD47 immunotherapy[44].

FUTURE DIRECTIONS

The pathogenesis and progression of BC are closely linked to the interaction between oxidative stress and inflammation and remain a major cause of morbidity and mortality in women worldwide. As BC is very heterogeneous, including hormone receptor-positive, HER2-positive, and TNBC, it is important to understand the underlying molecular mechanisms that drive its onset, progression, and resistance to treatment[45].

New therapeutic strategies use nanotechnology to deliver substances that modulate ROS levels in tumors. Lipid nanoparticles offer increased drug-loading capacity, stability, reduced toxicity, and improved targeting compared to traditional formulations[46]. In preclinical models, nanomaterials designed to produce cytotoxic ROS only in tumor cells are effective in disrupting the redox balance and inducing lipid peroxidation and oxidative damage to DNA and proteins[47]. These platforms can also be designed for combination therapies - e.g., chemotherapy- in which the release of doxorubicin-loaded platelets has been shown to induce immunogenic cell death in TNBC models by releasing DAMPs, which activate dendritic cells and promote antitumor immunity in combination with immune checkpoint blockade[48].

The complex interaction between oxidative stress and endoplasmic reticulum (ER) stress complicates BC pathophysiology. Accumulation of misfolded proteins in the ER lumen causes ER stress and triggers the unfolded protein response (UPR), which is designed to restore proteostasis. Through overlapping signaling pathways, ER stress and ROS production are closely related in multiple myeloma, a hematological malignancy similar to solid tumors. Through activation of the ER by ROS production in a self-sustaining cycle, prolonged ER stress can lead to apoptosis[49].

In highly metastatic BC such as TNBC, protein disulfide isomerase (PDI), an abundant ER enzyme involved in protein folding, was identified as a potential therapeutic target. PDI inhibition interferes with UPR signaling and induces apoptosis by sustained stress[50]. Physical activity and other lifestyle factors also influence BC risk and progression by altering the regulation of oxidative stress and inflammation. Exercise improves mitochondrial biogenesis in skeletal muscle, enhances antioxidant protection, reduces oxidative damage associated with aging, and reduces endothelial dysfunction. All these factors contribute to a healthier aging profile and may indirectly affect BC outcomes by altering the systemic redox state[51].

While fasting may not be feasible for cancer patients, it can be a beneficial tool in cancer prevention and treatment. Intermittent fasting exerts its effects by regulating circulating insulin and insulin-like growth factor-1 levels, metabolic and oxidative-inflammatory pathways, strengthening the autophagic process, and suppressing mTOR-dependent growth signaling. Metabolic adaptations contribute to reduced ROS production and NF-κB-mediated pro-inflammatory cytokines, facilitating the removal of damaged mitochondria. Clinical studies specifically in BC have shown that diets mimicking intermittent fasting during chemotherapy protect healthy tissues from treatment-related stress while increasing metabolic sensitivity in tumor cells, thereby enhancing the therapeutic efficacy and treatment sensitivity of chemotherapy drugs. Furthermore, the therapeutic efficacy of intermittent fasting in BC varies depending on tumor subtypes and treatment regimens and therefore requires further confirmation through well-controlled clinical trials.

Natural antioxidants are being studied for their potential role in reducing oxidative stress and inflammation in BC. Resveratrol, a polyphenol found in grapes, targets different components of TME by affecting the function of immune cells, angiogenesis, the activity of fibroblasts, and the remodeling of the extracellular matrix[52]. Plant chemicals found in fruits, vegetables, grains, and herbs have anti-inflammatory and antioxidant properties that can prevent degeneration of the intervertebral disc. This process has mechanistic similarity to tumor-induced inflammation. They are also being studied for their potential to modulate molecular pathways associated with carcinogenesis[53].

Natural products contribute to increased drug efficacy, reduced chemoresistance, and regulation of apoptosis, cell cycle, and autophagy through their anti-inflammatory and anticancer properties. In particular, polyphenols such as curcumin, resveratrol, epigallocatechin gallate, quercetin, and sulforaphane can induce tumor death by regulating autophagic flow through multiple molecular pathways, including AMPK-mTOR, PI3K-AKT-mTOR, SIRT1, Nrf2, and Beclin-1-dependent pathways. Resveratrol reduces mTOR activation and activates AMPK and SIRT1, leading to autophagosome formation and clearance of oxidatively damaged proteins and mitochondria. Polyphenols suppress mitochondrial ROS production via mitophagy and reduce NF-κB-dependent inflammatory signaling. In BC, autophagy is largely context-dependent. In early-stage tumor cells, autophagy limits oxidative damage, chronic inflammation, and genomic dysregulation.

In contrast, in advanced and aggressive tumors, it is used to tolerate hypoxia, nutrient deprivation, and therapeutic stress. Consequently, natural compounds increase anticancer efficacy by causing cytotoxic autophagy and disrupting the protective autophagic response that ensures tumor cell survival. Therefore, the biological effects of polyphenols are evaluated depending on the tumor subtype, stage, metastatic status, applied concentration, and duration of treatment[53].

The impact of the gut microbiota on redox balance and systemic inflammation has recently attracted attention. Short-chain fatty acids like butyrate, which are produced by gut microbial communities, have shown anticancer potential by influencing immune responses and metabolic pathways related to BC. These findings demonstrate the importance of considering host-microbe interactions when developing novel therapeutic strategies that address oxidative stress and inflammation[54].

CONCLUSION

The interplay between oxidative stress and chronic inflammation shapes almost all stages of BC development, progression, and response. Dysregulated redox and inflammatory pathways actively reprogram cancer cells and the TME, rather than being a by-product of tumor transformation. This promotes immune evasion, epithelial-mesenchymal transformation, metastasis, and resistance to systemic therapy, especially in aggressive subtypes such as triple-negative breast carcinoma. Combination panels of oxidative and inflammatory biomarkers, such as lipid peroxidation products, DNA and protein oxidation markers, cytokine profiles, and gene expression signatures, may improve risk stratification, prognostic evaluation, and prediction of response to chemotherapy, targeted therapy, and immunotherapy. However, due to tumor heterogeneity, context-dependent effects, and microenvironment barriers, therapeutic approaches aimed at altering redox balance or inflammatory signaling - such as Nrf2-directed approaches, nanotechnology-based ROS modulators, ferroptosis-inducing agents, and interventions targeting TAMs, CAFs, and immunometabolic reprogramming - have not yet translated into consistent clinical benefit.

Combining high-resolution molecular profiling of oxidative and inflammatory pathways with reliable clinical trial design, standardized biomarker platforms, and sensible combination regimens will be essential to turn these mechanistic findings into clinically useful tools in the future. These initiatives can ultimately lead to more precise prevention measures, early detection of high-risk conditions, and truly tailored treatment plans that exploit the redox and inflammatory vulnerability of the different molecular subtypes of BC.

ACKNOWLEDGEMENTS

The authors thank the Recep Tayyip Erdogan University Academic Language Editing Service, and they further used [ChatGPT-5.5] to improve the spelling and clarity of this manuscript. Şeyma Tutar acknowledges the Recep Tayyip Erdoğan University Development Foundation for awarding her the doctoral scholarship.