Immune evasion of advanced cancers is well studied, but little is known about this process in pre-malignant or early tumours. Goto et al. now find the transcription factor SOX17 to be essential in immune escape of adenomas and early colorectal cancers (CRCs).

Genetic depletion of Sox17 in tumour AKP organoids prevented growth in immunocompetent, but not immunodeficient, mice. In the few SOX17-null tumours that developed, a robust immune infiltration that was absent in control tumours was detected. Four weeks after transplantation, control tumours exhibited terminally exhausted CD8+ T cells as the prominent T cell cluster, whereas in SOX17-null tumours, effector-like CD8+ T cells with high expression of interferon-γ (Ifng) were the largest population identified. Within the CD4+ T cell compartment, regulatory T cells and T helper 1 (TH1) CD4+ T cells were dominant in control and SOX17-null tumours, respectively. Depletion of CD8+ T cells and to a lesser extent CD4+ T cells rescued engraftment of SOX17-null tumours, indicating that TH1 cells support effector CD8+ T cells to reject SOX17-null tumours. Mechanistically, SOX17 suppresses IFNγ signalling, which dampens antigen presentation and recruitment of CD8+ T cells, and deletion of the IFNγ receptor in SOX17-null tumours rescued their engraftment in mice.