Interferon-gamma (IFN-γ) is a pleiotropic cytokine with antiproliferative, pro-apoptotic, and antitumor properties. It is a major effector of immunity and has been used in the treatment of various diseases, although it has adverse effects. While there is broad evidence that IFN-γ is involved in tumor immune surveillance, IFN-γ-based therapies have had limited success in clinical trials. Recent studies suggest that IFN-γ may also have protumorigenic effects, such as through IFN-γ signaling, insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and checkpoint inhibitors. However, IFN-γ-mediated responses are still positively associated with patient survival in several cancers. Therefore, major research efforts are needed to understand the immune contexture in which IFN-γ induces its effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways. Keywords: type II interferon, immunoregulation, cancer microenvironment, immunotherapy, immune contexture.Interferon-gamma (IFN-γ) is a pleiotropic cytokine with antiproliferative, pro-apoptotic, and antitumor properties. It is a major effector of immunity and has been used in the treatment of various diseases, although it has adverse effects. While there is broad evidence that IFN-γ is involved in tumor immune surveillance, IFN-γ-based therapies have had limited success in clinical trials. Recent studies suggest that IFN-γ may also have protumorigenic effects, such as through IFN-γ signaling, insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and checkpoint inhibitors. However, IFN-γ-mediated responses are still positively associated with patient survival in several cancers. Therefore, major research efforts are needed to understand the immune contexture in which IFN-γ induces its effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways. Keywords: type II interferon, immunoregulation, cancer microenvironment, immunotherapy, immune contexture.