Therapeutic Implications in Improving the Tumor Microenvironment in Breast Cancer Treatment: An Update

Abstract

Among the leading causes of cancer-related morbidity and mortality worldwide, breast cancer presents fundamental challenges, such as tumor heterogeneity and therapeutic resistance. The tumor microenvironment (TME), comprising stromal components, signaling molecules, immune cells, and the extracellular matrix, has demonstrated a pivotal role in tumor progression, invasion, and therapeutic response. In this review, we comprehensively summarize the state-of-the-art and novel therapeutic strategies developed to reprogram the TME in breast cancer. From clinically established treatments, such as endocrine therapy, antibody-drug conjugates, and HER2-targeted therapy, to emerging agents, such as siRNA-mediated gene silencing, nanomedicine, and immunotherapy, each class of therapeutic strategy, along with the corresponding clinical and preclinical outcomes, is detailed by category. The evidence for and impact of TME heterogeneity and differences in molecular subtypes on therapeutic efficiency are highlighted, and biomarker-guided patient stratification is further emphasized to support precision therapy. Mechanistic challenges, such as immunosuppression, ECM remodeling, and hypoxia-associated resistance, were analyzed, and mechanistic conflicts or synergistic interactions between strategies were identified. Tumor microbiome modification and AIdriven discovery of novel biomarkers are presented as emerging perspectives in TME-targeting therapy. Despite significant advances, translation barriers, such as the lack of predictive biomarkers and the divergence in therapeutic outcomes between patients and animal models, are critically reviewed and discussed. The integration of TME-targeted and individualized therapeutic strategies may offer promising prospects toward achieving durable clinical outcomes in breast cancer treatment.