Tumour stromal cells support tumourigenesis. We report that Syndecan-2 (SDC2) is expressed on a non-epithelial, non-haematopoietic, non-endothelial stromal cell population within breast cancer tissue. In-vitro, syndecan-2 modulated TGFß signaling (SMAD7, PAI-1), migration and immunosuppression of patient-derived tumour-associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model overexpression of syndecan-2 in TASCs significantly enhanced TGFß signaling (SMAD7, PAI-1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFß signaling (SMAD7, PAI-1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan-2-peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFß-regulated immunosuppressive genes, such as CXCR4 and PD-L1. Moreover, using an orthotopic syngeneic breast cancer model overexpression of syndecan-2-peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan-2 within the TME inhibits tumour growth and metastasis due to decreased TGFß signaling and increased immune control. This article is protected by copyright. All rights reserved.