Abstract
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.
Highlights
Being identified as pivotal junctures of a multitude of pathways, signal transducer and activator of transcription (STAT) signaling mediates a vast array of processes that are required for homeostasis and development in mammals [1,2]
A succeeding conformational change that prevents inhibition by pseudokinase domains triggers the phosphorylation of resting STAT monomers in the cytoplasm, leading to homo- or heterodimerization and the formation of higher complexes, nuclear translocation, and DNA binding to specific palindromic sequences of target genes inducing their transcription and the further modulation of downstream targets [7]
There is a surprising lack of redundancy in Janus kinases (JAKs)-STAT signaling, given that several STATs may engage with the same DNA regulatory element (DRE), the same stimulus might activate multiple STATs, and heterogenous ligand interactions may act through the same STAT to induce differential downstream targets with disparate effects
Summary
Being identified as pivotal junctures of a multitude of pathways, signal transducer and activator of transcription (STAT) signaling mediates a vast array of processes that are required for homeostasis and development in mammals [1,2]. A succeeding conformational change that prevents inhibition by pseudokinase domains triggers the phosphorylation of resting STAT monomers in the cytoplasm, leading to homo- or heterodimerization and the formation of higher complexes, nuclear translocation, and DNA binding to specific palindromic sequences of target genes inducing their transcription and the further modulation of downstream targets [7]. These include many of the chemokines, caspases, interferon (IFN)-regulated genes (IRGs), growth factors, cyclin-dependent kinases, and metalloproteinases (MMPs) that are known to play a Cancers 2019, 11, 2002; doi:10.3390/cancers11122002 www.mdpi.com/journal/cancers. We investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense
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