Inflammation and cancer are linked by both oncogenic (intrinsic) and environmental (extrinsic) pathways. The intrinsic pathway is activated by genetic or epigenetic alterations in transformed cells. Such alterations include those that cause the overexpression or the persistent activation of growth factor receptors with intrinsic tyrosine kinase activity and cytokine receptors with associated Janus kinase (JAK) family tyrosine kinases. Oncogenic mutations in receptor-associated JAK family members also underlie some types of cancer. These receptors (several examples are shown), as well as non-receptor tyrosine kinases such as SRC, can be activated by extrinsic pathways — environmental factors that are associated with cancer inflammation — which include ultraviolet (UV) radiation, chemical carcinogens, infection, stress and cigarette smoke. Activated tyrosine kinases induced by both intrinsic and extrinsic pathways phosphorylate signal transducer and activator of transcription 3 (STAT3), which in turn forms dimers that translocate to the nucleus, where they directly regulate gene expression. In addition to upregulating numerous genes involved in proliferation, survival, invasion and metastasis, STAT3 induces the expression of many cytokines, chemokines and other mediators, such as interleukin-6 and cyclooxygenase 2, that are associated with cancer-promoting inflammation. Importantly, receptors for many of these cytokines, chemokines and mediators in turn further activate STAT3, thus forming autocrine and paracrine feedforward loops that result in a stable change to the genetic programme and the promotion of cancer inflammation. P, phosphorylation.

Myeloid cells, such as dendritic cells (DCs) and macrophages, can stimulate anti-tumour T helper 1 (T_H1) adaptive immunity and even cause direct tumour cell death, which is associated with the production of T_H1 cytokines, including interleukin-12 (IL-12) and interferon-γ (IFNγ). Activation of signal transducer and activator of transcription 1 (STAT1) (p-STAT1 denotes the activated phosphorylated form of STAT1) and STAT4 is important for anti-tumour T_H1 responses. However, tumour-associated macrophages (TAMs) harbouring activated STAT3 (p-STAT3) no longer exhibit anti-tumour effects in the tumour microenvironment. Instead, along with myeloid-derived suppressor cells (MDSCs), TAMs promote cancer progression when STAT3 is activated. Moreover, STAT3 activity in the tumour microenvironment contributes to the expression of pro-cancer inflammatory mediators and angiogenic and growth factors, leading to increased tumour growth. Both activated STAT3 and STAT6 also promote MDSC expansion. Similar STAT3-dependent factors are produced by tumour cells and endothelial cells, forming a crosstalk network among tumour myeloid cells, tumour cells and tumour endothelial cells important for tumour angiogenesis and metastasis.

Signal transducer and activator of transcription 1 (STAT1) signalling in T cells promotes T helper 1 (T_H1) differentiation and interleukin-12 receptor (IL-12R) expression. IL-12R signalling through STAT4 (p-STAT4 denotes the activated phosphorylated form of STAT4) further promotes T_H1 expansion, which leads to interferon-γ (IFNγ) expression. In the T_H1 milieu, adaptive immune responses control tumour growth. CD8⁺ T cells have a crucial role in cytotoxicity against tumour cells. Regulatory T (T_Reg) cells are important negative regulators of T_H1 anti-tumour immunity. STAT5 is crucial for T_Reg cell differentiation and expansion. Both STAT5 and STAT3 contribute to the expression of forkhead box P3, a marker for T_Reg cells. At the same time, STAT3 activation in tumour T_Reg cells promotes the expression of IL-10 and transforming growth factor-β (TGFβ), which are the mediators of T_Reg cell suppressive functions, leading to the downregulation of T_H1 anti-tumour immune responses. In the presence of increased IL-6, TGFβ and IL-23, all of which can be regulated by STAT3 in the tumour microenvironment, T_H17 T cells expand and produce IL-17. This IL-17 activates STAT3 in diverse immune cells and other stromal cells in the tumour microenvironment through IL-6, which can further promote tumour growth.

In normal physiology, nuclear factor-κB (NF-κB) is sequestered in the cytoplasm by inhibitor of NF-κBα (IκBα). When IκB kinases (IKKs) are activated by various pathogens and/or proinflammatory cytokines, IκBα is phosphorylated and degraded, allowing NF-κB nuclear translocation (). As a transcription factor, NF-κB (especially REL) upregulates many genes involved in stimulating T helper 1 (T_H1) immune responses that are necessary to control pathogens and to mediate anti-tumour immune responses. Several RELA downstream target genes encode factors that in turn activate signal transducer and activator of transcription 3 (STAT3) (). STAT3, which is also activated by intrinsic and extrinsic pathways, has the ability to inhibit IKK and thereby reduce NF-κB-associated T_H1 immunity. In addition, STAT3 contributes to the persistent activation of NF-κB during chronic inflammation and in transformed cells by prolonging nuclear retention of RELA. NF-κB–IκBα complexes can shuttle in and out of the nucleus in the absence of stimuli, although the rate of nuclear export is greater than that of nuclear import. STAT3 facilitates nuclear localization of RELA through p300 (also known as EP300)-mediated acetylation, which interferes with the NF-κB–IκBα interaction and prevents their nuclear export. When STAT3 activity is increased in tumours, NF-κB prefers the STAT3–p300 interaction. Although their cognate DNA-binding sites need not be immediately adjacent, NF-κB and STAT3 regulate the expression of numerous oncogenic and inflammatory mediators (). Many of these gene products in turn further activate STAT3. Therefore, STAT3 and NF-κB interact at multiple levels, thereby promoting cancer inflammation, restraining anti-tumour T_H1 immune responses and increasing tumour cell proliferation and survival as well as tumour angiogenesis and metastasis. P, phosphorylation; Ub, ubiquitylation.