The Interferon-Gamma Paradox in Cancer

Abstract

Interferon-gamma (IFNG) has long been implicated as a central orchestrator of antitumor immune responses in the elimination stage of the immunoediting paradigm. However, mounting evidence suggests that IFNG may also have important and significant protumor roles to play in the equilibrium and escape phases through its regulatory effects on immunoevasive functions that promote tumorigenesis. These seemingly contradictory effects of IFNG undoubtedly play profound roles in not only the activation of inflammatory response to cancer but also in the determination of its outcome. In the face of the recent explosion of anticancer immunotherapeutic strategies in the clinic, it is critical that a complete understanding is achieved of the underpinnings of the mechanisms that determine the two faces of IFNG signaling in cancer. Here, the current state of this dichotomy is reviewed.

Keywords: cancer; cytokine signaling; immunoediting; immunoevasion; immunosurveillance; interferon-gamma.

FIG. 1.

Putative mechanisms of the antitumor and protumor roles of IFNG in the tumor microenvironment. IFNG signaling affects both the immune cells and tumor cells. Which face of IFNG dominates in a particular tumor microenvironment is likely dependent on the tumor-type specificity, local signal intensity, and/or other microenvironmental cues. IFNG, interferon-gamma.