Revisiting STAT3 signalling in cancer: new and unexpected biological functions

The Janus kinases (JAKs) are major activators of signal transducer and activator of transcription (STAT) proteins. JAK–STAT3 signalling is crucial for cancer development in both tumour cells and the tumour microenvironment, and both JAK and STAT3 have emerged as important targets for cancer treatment.Interleukin-6 (IL-6) and several other members of the IL-6 family have a prominent role in JAK–STAT3 activation in cancer. Antibodies that target IL-6 are currently in clinical trials for cancer treatment. However, owing to a multitude of cytokines, growth factors and many other molecules that activate JAK–STAT3, blocking IL-6 and its family members alone is not likely to be sufficient for cancer treatment.Several G-protein-coupled receptors (GPCRs) are found to activate STAT3 through JAKs, leading to cancer progression. GPCRs are more readily druggable than STAT3, which is a transcription factor and therefore difficult to target because it is mostly in the nucleus and lacks enzymatic activity.Although Toll-like receptors (TLRs) are usually associated with immune activation, several of them are overexpressed and could promote cancer via the JAK–STAT3 pathway in both immune cells and tumour cells. The synthetic ligand of TLR9A, CpG oligonucleotide, when linked to small interfering RNA (siRNA) against STAT3, has been shown to be an effective approach to deliver RNA into both immune cells and tumour cells. The CpG–STAT3 siRNA is now poised to enter clinical trials for cancer treatment.Some microRNAs that interact with the JAK–STAT3 pathway are emerging as having crucial roles in regulating cancer-promoting inflammation and oncogenesis. Appropriate microRNAs that can block the JAK–STAT3 pathway could potentially be developed as inhibitors of this pathway with clinical application.Although STAT3 is well known as a transcription factor that defines a gene expression programme in cancer, recent studies have identified surprising roles of STAT3 in mitochondria in cancer. Importantly, STAT3 also contributes to cancer progression by DNA methylation and chromatin topological modulation.