Immunotherapies that harness the immune system against cancer are an attractive proposition for cancer treatment. While there have been some promising successes, only a small fraction of patients obtain clinical benefit. It has become clear that the immunosuppressive tumour microenvironment (TME) is a major obstacle for immunotherapies, because the TME suppresses immune responses leading to reduced efficacy. We previously demonstrated that the site of tumour growth is a major determinate in sculpting the organ-specific TME, and thus predisposes treatment efficacy1. In this project, we hypothesise that the TME of visceral tumours is more immunosuppressive than the ones of the tumours growing elsewhere. We investigated in murine models the difference in the TME in breast cancer growing orthotopically and the same breast cancer growing in the common metastatic sites, such as the lungs. Our findings showed that the breast cancer growing in the lungs were resistant to immunotherapies whereas the breast cancer growing orthotopically could be completely eradicated even when the cancer burden was greater. Through an institutional prospective community-based rapid autopsy program (CASCADE), we obtained genetically matched metastases from several sites in the same breast cancer patients and investigated the TME from these tumours using novel technologies such as RNAseq and multiplex immunohistochemistry. Strikingly, the TMEs from the same organs in different patients have similar immune gene expression profiles and in contrast, TMEs from the same patient differ greatly in different organs. Together, our research demonstrates an organ-specific difference between TMEs that leads to different responses to therapies. We anticipate that further study of how cancer cells sculpt the TME at different sites will greatly enhance our understanding of the TME and provide promising targets to enhance current immunotherapies, especially for patients that do not respond to existing therapies.