Resistance to neoadjuvant chemotherapy in breast cancers: a metabolic perspective

Neoadjuvant chemotherapy (NAC) is a cornerstone in the treatment of early-stage high-risk breast cancers (BC), particularly in triple-negative, HER2-positive, and selected hormone receptor-positive subtypes. However, its effectiveness is frequently hindered by intrinsic or acquired resistance, resulting in a significant residual cancer burden (RCB) in more than half of patients. Despite extensive genomic profiling, reliable predictive biomarkers for treatment response remain limited, impeding the development of personalized therapeutic strategies. Emerging evidence highlights tumor metabolic reprogramming as a key non-genetic mechanism contributing to NAC resistance. In this review, we critically examine current advances in metabolic imaging and metabolomics as tools to predict NAC response in BC. We also discuss the role of the tumor microenvironment (TME), including hypoxia and acidosis, in shaping metabolic plasticity and fostering treatment resistance. Furthermore, we explore novel therapeutic strategies targeting metabolic pathways, ranging from enzyme inhibition to dietary interventions, and the use of advanced preclinical models. Together, these insights offer a metabolic framework for overcoming NAC resistance and advancing precision oncology in early-stage BC.