Abnormal activation of signal transducer and activator of transcription 3 (STAT3) transcription factor has been observed in many human cancers with roles in tumor initiation, progression, drug resistance, angiogenesis and immunosuppression.
Furthermore, Western blot analysis showed that higher immunosuppression decreased phosphorylation of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells-p65, increased phosphorylation of extracellular-signal-regulated kinase, and reduced the expression of Bcl-2-associated X protein and caspase-3 in the renal allografts.
Apart from its oncogenic role in regulating gene expression in tumor cells, STAT3 also paves the way for human cancer growth through immunosuppression.
However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.
STAT3 is considered to be a key molecule to mediating tumor-induced immunosuppression in various manners at tumor sites, by acting through immune-regulatory cytokines derived from the tumor cells.
CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival.
In in vitro and in vivo studies, including studies on humans, selective STAT3 inhibitors such as Stattic and S3I-201 have demonstrated potential in regulating MDSC-mediated immunosuppression.
STAT3-dependent VEGF production from keratinocytes abrogates dendritic cell activation and migration by arsenic: a plausible regional mechanism of immunosuppression in arsenical cancers.
Upon upregulating miR-124 in glioma cancer stem cells (gCSC), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immunosuppression of T-cell proliferation and induction of forkhead box P3 (Foxp3)(+) regulatory T cells (Treg).
The activation of signal transducer and activator of transcription signaling 3 (STAT3) has been linked with the survival, proliferation, angiogenesis and immunosuppression of hepatocellular carcinoma cells (HCCs).