Collagen dynamics in the breast cancer tumor microenvironment and therapeutic perspectives.

Breast Cancer (BC) remains one of the most prevalent malignancies among women globally, with its pathogenesis and clinical progression being profoundly regulated by the tumor microenvironment (TME). Collagen, the most abundant extracellular matrix (ECM) component, plays multifaceted roles in shaping the TME of BC. Aberrant cllagen deposition, crosslinking, and remodeling alter tissue stiffness and architecture, driving tumor initiation, growth, invasion, and metastasis through integrin and discoidin domain receptor-mediated mechanosignaling, growth factor regulation, and metabolic reprogramming. Collagen rich stroma also acts as a physical and biochemical barrier that restricts T cell infiltration, promotes macrophage polarization, and impairs natural killer cell (NK) cytotoxicity, thereby facilitating immune evasion and therapeutic resistance. Specific collagen isoforms, including types I, III, V, VI, X, and XI, exhibit context-dependent tumor promoting or tumor restraining effects, underscoring the complexity of roles. Recent advances in targeting collagen biology, such as enzymatic degradation, inhibition of crosslinking enzymes, blockade of collagen receptors, and immune modulation strategies demonstrates promising preclinical results, with several approaches progressing to clinical trials. Future perspectives emphasize the integration of collagen targeting therapies with immunotherapy and chemotherapy, alongside the development of predictive biomarkers to stratify patients most likely to benefit. Collectively, collagen represents both a critical regulator of BC pathogenesis and a promising therapeutic target with significant translational potential.