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

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.