Constitutive expression of interferons (IFNs) and activation of their signaling pathways have pivotal roles in host responses to malignant cells in the tumor microenvironment. IFNs are induced by the innate immune system and in tumors through stimulation of Toll-like receptors (TLRs) and through other signaling pathways in response to specific cytokines. Although in the oncologic context IFNs have been thought of more as exogenous pharmaceuticals, the autocrine and paracrine actions of endogenous IFNs probably have even more critical effects on neoplastic disease outcomes. Through high-affinity cell surface receptors, IFNs modulate transcriptional signaling, leading to regulation of more than 2,000 genes with varying patterns of temporal expression. Induction of the gene products by both unphosphorylated and phosphorylated STAT1 after ligand binding results in alterations in tumor cell survival, inhibition of angiogenesis, and augmentation of actions of T, natural killer (NK), and dendritic cells. The interferon-stimulated gene (ISG) signature can be a favorable biomarker of immune response but, in a seemingly paradoxical finding, a specific subset of the full ISG signature indicates an unfavorable response to DNA-damaging interventions such as radiation. IFNs in the tumor microenvironment thus can alter the emergence, progression, and regression of malignancies.
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