Metabolic crosstalk in breast cancer in patients with Type 2 diabetes mellitus: pathophysiology and nanotherapeutic opportunities for clinical translation.

The intersection of Type 2 Diabetes Mellitus (T2DM) and breast cancer defines a complex onco-metabolic axis where chronic hyperglycaemia, hyperinsulinemia, and oxidative stress synergistically drive malignant transformation, metabolic reprogramming, and chemoresistance. Despite epidemiological evidence linking these conditions, clinical management typically addresses each disease individually according to established protocols; however, the presence of T2DM significantly alters tumour biology, therapeutic response, and outcomes, necessitating greater consideration of metabolic context in breast cancer treatment. This review delineates the molecular underpinnings of the T2DM-breast cancer comorbidity and critically evaluates current metabolism-targeted therapies within this context. We examine the limitations of current therapeutic strategies in addressing the bidirectional metabolic signalling sustaining both pathologies, thereby motivating the exploration of nanoparticle (NP)-mediated therapeutic approaches. NP strategies enable tumour-selective release, dual-action antidiabetic and anticancer payload delivery, and targeted modulation of shared metabolic pathways are surveyed. Additionally, we highlight how NP platforms can be engineered as intrinsically bioactive scaffolds that synergise with multitarget natural compounds, with potentially lower-toxicity, multi-functional therapeutic strategies suited to this complex comorbid condition. We advocate for systematic investigation of dual-action nanotherapeutics in models of breast cancer in patients with T2DM as a necessary step toward a unified approach for this underserved comorbid population.