Breast cancer is the second leading cause of cancer-related death in women and metastases are more deadly than primary tumours, yet the development of anti-metastatic therapies has been hampered by a limited understanding of the underlying biology and a subsequent lack of drug targets. One area of cancer biology that shows promise in identifying new drugable targets is the tumour microenvironment. We identified and characterized a subpopulation of pro-tumoural macrophages: the Tie2-expressing monocytes/macrophages (TEMs) endowed with pro-angiogenic and immunosuppressive activities. These data also suggested that both activities might be regulated by the TIE2 ligand ANG2, a cytokine highly expressed in tumours. We demonstrated for the first time that targeting the ANG2/TIE2 pathway inhibits tumour angiogenesis, growth, and metastasis. In addition, we showed that blocking the ANG2/TIE2 pathway disables the pro-angiogenic activity of TEMs thus impeding the emergence of evasive resistance to anti-angiogenic therapy1 . We are now investigating whether the in vivo blockade of ANG2 in not only inhibiting the pro-angiogenic activity of TEMs, but also reverting their immunosuppressive activity, thus providing a strong rational for the development and testing of new combination therapies. The establishment of an immunosuppressive tumour microenvironment is one of the hallmarks of cancer and the major impediment to the successful application of anti-tumour immunotherapy. As an alternative strategy aimed at reverting the immunosuppressive microenvironment, we developed a cell- and gene-based delivery therapy able to inhibit primary and metastatic breast cancer in mouse and human hematochimeric models upon genetic engineering of human hematopoietic stem cells for targeted delivery of Interferon-α by tumor-infiltrating macrophages2,3. We are now combining this strategy with other immunotherapeutic approaches to best exploit the biological weapons of immunity and provide proof-of-feasibility of new therapy strategies.