THBS2: the key hub linking breast cancer stroma, immunity, and therapeutic response.

Thrombospondin-2 (THBS2) has emerged as a pivotal yet paradoxical regulator within the breast cancer (BC) tumor microenvironment (TME). This review synthesizes current evidence to elucidate its context-dependent duality and its potential as a novel therapeutic target. While THBS2 can function as a tumor suppressor by inhibiting angiogenesis, it more frequently exhibits pro-tumorigenic activities in aggressive subtypes like triple-negative breast cancer (TNBC). Here, THBS2, predominantly secreted by cancer-associated fibroblasts, drives metastasis by activating key oncogenic pathways including PI3K/AKT, Notch, and Wnt/β-catenin, thereby promoting epithelial-mesenchymal transition (EMT) and stemness. Its expression and functional output are further complicated by competitive endogenous RNA (ceRNA) network regulation, explaining contradictory clinical associations. Crucially, THBS2 is a key architect of an immunosuppressive "cold" TME. It constructs dual barriers: a physical barrier through extracellular matrix remodeling that impedes T-cell infiltration, and a chemical barrier by potentially suppressing CD36⁺ T-cell function. Consequently, therapeutic inhibition of THBS2 presents a promising integrative "cold-to-hot" conversion strategy. By simultaneously dismantling stromal architecture and alleviating local immune suppression, targeting THBS2 could enhance T-cell trafficking and reactivate anti-tumor immunity, potentially overcoming resistance to current immunotherapies. Future research must adopt a network-based approach to decipher THBS2's contextual roles and translate its targeting into effective combination strategies for advanced breast cancer.