Work

The neuro–metabolic–immune axis in breast cancer: emerging mechanisms and subtype-specific therapeutic opportunities

Year: 2026

Type: review

Abstract: Tumor innervation is increasingly recognized as an active component of the breast tumor microenvironment, where neural signals influence cancer cells, stromal populations, and immune responses through neurotransmitters, neuropeptides, and neurotrophic factors. Sympathetic, cholinergic, and sensory pathways can regulate tumor growth, migration, stromal remodeling, and immune activity, while neural signaling also intersects with tumor metabolism by modulating glycolysis, lipid mobilization, and amino acid utilization. Metabolic changes, including lactate accumulation and histone lactylation, may further reshape tumor and immune-cell states, linking neural activity with metabolic adaptation and immune regulation. These interactions vary across breast cancer subtypes, with adrenergic and sensory-neuropeptide signaling implicated in triple-negative breast cancer, metabolic adaptation during HER2-targeted therapy, and neurotrophic and adipose-tumor crosstalk in hormone receptor-positive/HER2-negative disease. We apply the recently proposed concept of the neuro-metabolic-immune axis to breast cancer, systematically evaluating the strength of evidence for each component and organizing the discussion by molecular subtype and therapeutic maturity. We further discuss therapeutic opportunities ranging from β-adrenergic and neuropeptide pathway modulation to downstream metabolic targeting, while distinguishing direct neural mechanisms from indirect or complementary evidence.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1890810