Biomaterial-based mitochondria-targeted nanomedicine for remodeling the breast cancer tumor microenvironment and overcoming therapy resistance.

Abstract

Breast cancer treatment remains limited by therapeutic resistance, recurrence, and incomplete responses to immunotherapy, largely because tumor cells continuously adapt to the dynamic tumor microenvironment (TME). Mitochondria are central regulators of energy metabolism, redox balance, cell death, inflammatory signaling, and immune modulation. Stressors within the breast cancer TME, including hypoxia, nutrient deprivation, acidosis, matrix stiffening, oxidative stress, and treatment pressure, can remodel mitochondrial metabolism and dynamics, thereby promoting tumor survival, invasion, immune evasion, and therapy resistance. Conversely, stressed mitochondria reshape the TME through metabolic byproducts, reactive oxygen species, mitochondrial DNA release, inflammatory mediators, and stromal or vascular remodeling signals. This reciprocal mitochondria-TME crosstalk forms a self-reinforcing pathological loop that supports breast cancer progression. Biomaterial-based mitochondria-targeted nanomedicine offers a strategy to intervene in this loop by integrating multilevel delivery, microenvironment-responsive release, mitochondrial targeting, metabolic regulation, and immune activation. This review summarizes how the breast cancer TME remodels mitochondrial function, how mitochondrial stress reciprocally reshapes the TME, and how biomaterial-based therapeutic platforms can be designed to target this axis. We further discuss translational challenges, including tumor specificity, intratumoral penetration, long-term biosafety, subtype-specific intervention, and clinically relevant combination strategies.