The Yin and Yang of Type I IFNs in Cancer Promotion and Immune Activation

SIMPLE SUMMARY: The crucial immune stimulatory functions exerted by Type I Interferons (IFNs) in cancer settings have been not only widely demonstrated during the last fifty years but also recently harnessed for therapy. However, depending on the dose and timing, and the downstream induced signatures, Type I IFNs can and do foster cancer progression and immune evasion. Dysregulations of Type I IFN signaling cascade are more and more frequently found in the tumor microenvironment, representing critical determinants of therapeutic innate and adaptive resistance to several anticancer treatments. Understanding when and through which genetic signatures Type I IFNs control or promote cancer growth is extremely urgent in order to prevent and by-pass the deleterious clinical effects and develop optimized innovative (combinatorial) strategies for an effective cancer management. ABSTRACT: Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune“logical” way to exploit these cytokines for anticancer therapy.