The Dual Role of TLR2 in Breast Cancer: Implications for Therapeutic Targeting.

Abstract

Background: Breast cancer (BC) remains a leading cause of cancer-related mortality because of its molecular heterogeneity, recurrence, and resistance to systemic therapies. Toll-like receptor 2 (TLR2) has emerged as a key regulator of both tumor cell signaling and the tumor microenvironment, making it a promising therapeutic target.Objective: This review summarizes the biological functions, clinical significance, and therapeutic potential of TLR2 in BC, with emphasis on its context-dependent effects across different cellular compartments.Methods: We reviewed current experimental and clinical evidence on TLR2 signaling, expression patterns, immune regulation, and therapeutic targeting in BC, integrating findings from tumor biology, immunology, and translational studies.Results: TLR2 signals primarily through the TIRAP/MYD88 pathway to activate NF-κB, MAPK, and, under specific conditions, IRF7-related pathways. Its biological effects depend on molecular subtype, ligand source, cellular context, and activation kinetics. Persistent TLR2 activation in tumor cells, cancer stem-like cells, suppressive myeloid cells, fibroblasts, and metastatic niches promotes stemness, epithelial-mesenchymal transition, metastasis, therapeutic resistance, and immune evasion. Conversely, selective activation in conventional type 1 dendritic cells and appropriately polarized macrophages enhances antigen presentation, cytotoxic T-cell priming, and antitumor immunity.Conclusions: TLR2 functions as a context-dependent immune-state switch rather than a uniformly pro-or antitumor receptor. Biomarker-guided strategies that selectively inhibit tumor-promoting TLR2 signaling while preserving or enhancing immune-activating functions may improve precision immunotherapy for BC.