How tumours escape the immune system is not well defined. Nirschl et al. show that immune phagocytes in human melanoma share a physiological gene signature, which co-enriches and correlates with interferon-γ (IFNγ)-directed gene transcripts, and which is induced across multiple human cancers. Suppressor of cytokine signalling 2 (SOCS2) was highly expressed in melanoma-infiltrating mononuclear phagocytes and required for immune escape. SOCS2 loss in vivo led to robust immune-mediated tumour rejection. This indicates that SOCS2, as part of an IFNγ-induced tissue signature, mediates peripheral immune surveillance, and this is exploited by tumours.