Abstract
Type I interferon (IFN) has long been known as a critical component of the molecular machinery that first responds to viral infection in multicellular eukaryotes. More recently, type I IFN signaling has also emerged as a common process in the microenvironment of naturally developing neoplasms, as well as tumors responding to (immuno)therapy. In this setting, robust, acute but ultimately resolving type I IFN responses appear to support natural and therapy-driven cancer immunosurveillance by a number of mechanisms, including an accrued propensity of malignant cells to arrest their proliferation and undergo apoptotic cell death, as well as broad immunostimulatory effects on CD8(+) cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, dendritic cells (DCs) and tumor-associated macrophages (TAMs). Conversely, weak, indolent and ultimately non-resolving type I IFN responses de facto facilitate tumor progression, not only by promoting stemness in malignant cells (which is associated with increased metastatic dissemination and resistance to therapy), but also by favoring the establishment of a highly immunosuppressive lymphoid and myeloid tumor microenvironment. Here, we provide a critical discussion of the context-dependent impact of type I IFN signaling on cancer progression and response to treatment, focusing on the tumor-intrinsic and extrinsic factors that may account for such a heterogeneity.