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

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.

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.

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.