Paracrine networks driving heterogeneity and therapy resistance in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by marked heterogeneity, early metastasis, and frequent therapeutic resistance. These features are increasingly recognized as products of dynamic communication among malignant, immune, stromal, and vascular cells within the tumor microenvironment. In this review, we propose a framework of paracrine network-driven niche evolution in TNBC. Single-cell and spatial omics reveal that TNBC is organized into spatially distinct cellular niches maintained by soluble factors and extracellular vesicles. These communication modalities are further reinforced by feedback amplification, therapy-induced rewiring, and microenvironmental memory. Together, they promote tumor-cell plasticity and metastatic competence, immune dysfunction, vascular and metabolic remodeling, and adaptive therapeutic resistance. We also discuss therapeutic strategies targeting cytokine, chemokine, stromal, vascular, and extracellular-vesicle-mediated communication, as well as current challenges in functional validation, biomarker development, and clinical translation. TNBC progression and treatment failure should be understood as emergent consequences of spatially organized and temporally rewired paracrine networks rather than tumor cell-intrinsic events alone. Targeting dominant communication dependencies may provide a rational basis for biomarker-guided combination therapies.