Breast cancer and metabolic comorbidities: From epidemiology and molecular mechanisms to precision interventions

Table 1 Clinical implications of metabolic comorbidities throughout the breast cancer care continuum

Clinical dimension	Obesity	Type 2 diabetes	Metabolic syndrome	Cardiovascular disease
Tumour pathology and subtype	Associated with postmenopausal ER+ disease; central obesity linked to luminal B/TNBC in younger[125,127]	Higher incidence of TNBC; lower prevalence of HER2+ disease[54]	Potentially stronger association with poor prognosis in HER2-overexpressing subtypes[61]	-
Treatment delivery and efficacy	Therapeutic decisions: Contributes to treatment de-escalation in older adults[98,132]	Therapeutic decisions: Lower likelihood of receiving chemotherapy[55]	Efficacy: Lower pCR rates after NACT[60,62]	Therapeutic decisions: Contributes to undertreatment, particularly in metastatic HER2+ disease[131]
	Efficacy: Reduced rate of pCR following NACT[42,62]	Safety: Increased risk of postoperative complications[14,49]		Safety: Key predictor of CTRCD; CDK4/6 inhibitors increase risk of hypertension and MACE[71,77,78]
Long-term survival outcomes	Recurrence: Increased risk, especially in HR+ patients on aromatase inhibitors[35,135]	Second primary cancers: Elevated risk of several SPCs (e.g., liver, brain)[16]	Recurrence: Significantly increased risk[12,60]	Mortality: Leading cause of non-cancer death among survivors[67,68]
	Mortality: Elevated breast cancer-specific and all-cause mortality[9,26,136]	Mortality: 20% increased risk of breast cancer-related death; causal evidence exists[10,51]	Mortality: Elevated breast cancer-specific and all-cause mortality[12,60]

ER+: Estrogen receptor-positive; TNBC: Triple-negative breast cancer; pCR: Pathological complete response; HER2: Human epidermal growth factor receptor 2; SPCs: Second primary cancers; pCR: Pathological complete response; NACT: Neoadjuvant chemotherapy; CTRCD: Cancer therapy-related cardiac dysfunction; MACE: Major adverse cardiovascular events.

Table 2 Mechanistic interplay between metabolic dysregulation and breast cancer, and emerging therapeutic strategies

Biological scale	Core pathophysiological process	Key molecular mediators and pathways	Potential intervention strategies
Systemic and microenvironmental	Adipose tissue dysfunction: Promotes chronic inflammation via adipokine/cytokine secretion[4,29]	Leptin, IL-6, TNF-α; TREM2; collagen deposition[4,19,29,103,105]	Lifestyle: Weight loss reverses obesity-associated immunosuppression[104]
	Immune suppression: Enrichment of M2 macrophages and MDSCs in the TME[19,101,104]		Pharmacological: GLP-1 receptor agonists (e.g., semaglutide)[21,22]
	Extracellular matrix remodelling: Favours tumour invasion and metastasis[103]		Immunotherapy: Combination with checkpoint inhibitors[19,101,104]
Cellular and signalling	Metabolic pathway hyperactivation: Drives cell proliferation and survival[6,17]	PI3K/Akt/mTOR; JAK/STAT; Wnt/β-catenin[6,17,101,109,110,112]	Drug repurposing: Metformin[11,22]
	Persistent inflammatory signalling: Fuels tumour progression[109,110]		Targeted therapies: PTP1B inhibitors (dual-target); PI3K/AKT inhibitors (e.g., alpelisib, capivasertib)[56,57,119]
	Developmental pathway dysregulation: Contributes to oncogenesis[101,112]		Natural compounds: Genistein (soy isoflavone)[101]
Epigenetic and molecular	Metabolite-driven reprogramming: Alters gene expression via histone modifications and DNA methylation[51,53]	H3K27ac at MCM5 promoter; MMP-9 promoter demethylation; miR-877-5p[51,53,64]	Epigenetic drugs (in development): Strict metabolic control RNA-based therapies (potential)
	Non-coding RNA dysregulation: Connects metabolic stress to cancer phenotypes[64]
Emerging frontiers	Gut-microbiota-host crosstalk: Microbial dysbiosis and metabolites systemically influence immunity and cancer progression[19,65]	Microbiota-derived leucine; FOXA1/GAL3ST1 axis[19,124]	Microbiome modulation: Pre/probiotics, faecal microbiota transplantation[114]
	Sphingolipid metabolic reprogramming: Identified in obesity-associated TNBC[124]		Natural compounds: Astragaloside IV[124]

MDSCs: Myeloid-derived suppressor cells; TME: Tumour microenvironment; IL-6: Interleukin-6; TNF: Tumor necrosis factor; TREM2: Triggering receptor expressed on myeloid cells 2; GLP-1: Glucagon-like peptide-1; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; mTOR: Mammalian/mechanistic target of rapamycin; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; PTP1B: Protein tyrosine phosphatase 1B; H3K27ac: Histone H3 lysine 27 acetylation; MCM5: Minichromosome maintenance complex component 5; MMP-9: Matrix metalloproteinase-9; FOXA1: Forkhead box A1; GAL3ST1: Galactose-3-O-sulfotransferase 1; TNBC: Triple-negative breast cancer.