Roles of IFN-γ in tumor progression and regression: a review

Background Interferon-gamma (IFN-gamma) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-gamma is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-gamma may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-gamma in the tumor microenvironment (TME) may be misleading in terms of its clinical application. Main body Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-gamma in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-gamma acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-gamma signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. Conclusion Significant research efforts are required to decipher IFN-gamma-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-gamma in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-gamma responsive patients to improve their sensitivity to immuno-therapies.