Interferon-γ: teammate or opponent in the tumour microenvironment?

Cancer immunotherapy offers substantive benefit to patients with various tumour types, in some cases leading to complete tumour clearance. However, many patients do not respond to immunotherapy, galvanizing the field to define the mechanisms of pre-existing and acquired resistance. Interferon-gamma (IFN gamma) is a cytokine that has both protumour and antitumour activities, suggesting that it may serve as a nexus for responsiveness to immunotherapy. Many cancer immunotherapies and chemotherapies induce IFN gamma production by various cell types, including activated T cells and natural killer cells. Patients resistant to these therapies commonly have molecular aberrations in the IFN gamma signalling pathway or express resistance molecules driven by IFN gamma. Given that all nucleated cells can respond to IFN gamma, the functional consequences of IFN gamma production need to be carefully dissected on a cell-by-cell basis. Here, we review the cells that produce IFN gamma and the different effects of IFN gamma in the tumour microenvironment, highlighting the pleiotropic nature of this multifunctional and abundant cytokine. Vignali and colleagues discuss the pleiotropic roles of interferon-gamma (IFN gamma) in the tumour microenvironment; on the one hand, it acts as a 'teammate' to promote antitumour immune responses and, on the other hand, it acts as an 'opponent' promoting tumour growth and suppressing immune responses.