STATs in cancer inflammation and immunity: a leading role for STAT3

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Abstract
Signal transducer and activator of transcription (STAT) proteins have dual roles: they transduce signals through the cytoplasm and function as transcription factors in the nucleus. Although some STAT proteins such as STAT1 increase anti-tumour immunity, STAT3 and others induce cancer-promoting inflammation. STAT3 signalling is a major intrinsic pathway for cancer inflammation owing to its frequent activation in malignant cells and key role in regulating many genes crucial for cancer inflammation in the tumour microenvironment. Persistent activation of STAT3, and to a lesser extent STAT5, in diverse human cancers increases proliferation, survival, angiogenesis and metastasis, while also inhibiting anti-tumour immunity. Many STAT3-regulated genes encode cytokines and growth factors, the receptors of which in turn activate the same STAT3 pathways, thereby propagating a stable feedforward loop between tumour cells and non-transformed stromal cells, including myeloid cells and T cells, promoting inflammatory responses that further support tumour growth and survival. Interleukin-6 (IL-6)–Janus kinase (JAK)–STAT3 signalling is important for cancers resulting from the activation of the intrinsic inflammatory pathway owing to genetic or epigenetic changes in tumour cells. Extrinsic environmental inflammatory factors such as sunlight, pathogens and chemical carcinogens can also activate STAT3 through different mechanisms. STAT3 interacts with nuclear factor-κB (NF-κB) at multiple levels and is activated by several NF-κB-regulated gene products, including IL-6. These two transcription factors regulate a multitude of genes important for STAT3 activation and cancer-promoting inflammation. STAT1-driven anti-tumour immune responses and STAT3-mediated immune modulatory pathways can be mutually antagonistic, suggesting that therapeutic interventions targeting specific STATs can tip this balance to convert tumour-promoting inflammation to anti-tumour immune responses. Therefore, STAT3 has emerged as a crucial target for cancer therapy and STAT3 inhibitors are actively being developed. Several tyrosine kinase inhibitors already in the clinic reduce STAT3 signalling by various mechanisms, thereby inducing tumour cell apoptosis and modulating inflammation in the tumour microenvironment in favour of therapeutic responses.