Breast cancer (BC) is the most common malignant tumor in women. There are different risk characteristics and treatment strategies for different subtypes of BC. The tumor microenvironment (TME) is of great significance for understanding the occurrence, development, and metastasis of tumors. The TME plays an important role in all stages of BC metastasis, immune monitoring, immune response avoidance, and drug resistance, and also plays an important role in the diagnosis, prevention, and prognosis of BC. Smart nanosystems have broad development prospect in the regulation of the BC drug delivery based on the response of the TME. In particular, TME-responsive nanoparticles cleverly utilize the abnormal features of BC tissues and cells to achieve targeted transport, stable release, and improved efficacy. We here present a review of the mechanisms underlying the response of the TME to BC to provide potential nanostrategies for future BC treatment.