Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer. Display omitted •A myeloid-rich, T-cell-poor immunosuppressive microenvironment promotes metastasis•Genetically engineered myeloid cells (GEMys) deliver IL-12 to metastatic sites•IL12-GEMys reverse immune suppression and activate anti-tumor immunity•Chemotherapy with IL12-GEMy treatment achieves durable cures in pre-clinical models Genetically engineered myeloid cells expressing IL-12 can reverse the immunosuppressive environment developed during metastatic progression by augmenting T cell responses and reducing metastatic burden in preclinical models.