Bidirectional regulatory network between tumor microenvironment and breast cancer drug resistance with innovative targeted therapy strategies

Therapy resistance constitutes the core bottleneck restricting improved prognosis in breast cancer (BC) patients. As the essential survival niche for tumor cells, the tumor microenvironment (TME) has emerged as a pivotal regulatory system mediating therapeutic resistance in BC. Traditional studies have focused on intrinsic resistance mechanisms of tumor cells while neglecting the dynamic bidirectional crosstalk between the TME and BC cells. This review systematically characterizes the forward regulatory mechanisms by which TME components (immune cells, stromal cells, and physicochemical factors) drive BC resistance through immunosuppression, stromal activation, and microenvironment remodeling, as well as the core pathways through which drug-resistant BC cells reversely reshape the TME via cytokine secretion, metabolic reprogramming, and extracellular matrix (ECM) remodeling. The molecular hub roles of cytokine signaling, metabolic reprogramming, and signaling pathway crosstalk in bidirectional regulation are deeply dissected. On this basis, innovative therapeutic strategies targeting this bidirectional network are comprehensively summarized, including tumor cell–TME dual-targeted combination therapy, TME functional remodeling strategies, and TME-responsive nanodrug delivery systems, together with their clinical translation progress and key clinical trial data. Finally, in view of the challenges faced by current TME-targeted therapy, such as TME heterogeneity, off-target effects, and an incomplete biomarker system, future research directions and clinical translation priorities are prospected combined with emerging technologies including single-cell spatial omics, artificial intelligence (AI), and personalized vaccines. While acknowledging that most TME-targeted strategies remain at the preclinical or early clinical stage, with a substantial translational gap between murine-model efficacy and confirmed patient benefit, this review provides a novel theoretical framework for overcoming BC resistance and lays a critical, balanced foundation for developing efficient and precise personalized TME-targeted therapeutic strategies. Furthermore, ferroptosis-targeted TME remodeling, CAR-T cell therapy, and oncolytic virus (OV) therapy are integrated into the bidirectional regulatory framework as mechanistically defined intervention nodes rather than isolated outlook topics.