Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.

Keywords: Cancer; Immunosuppression; Inhibitors; Metabolic reprogramming; Modulators; STAT3.

Fig. 1

STAT3 structure and the canonical and non-canonical STAT3 signaling pathways in cancer. A Diagrams of structure and function domains of STAT3 with the posttranslational modification residue sites. STAT3 is composed of an N-terminal domain (NTD), DNA binding domain, linker domain, Src homology 2 domain (SH2), and a C-terminal transactivation domain (TAD) with a tyrosine phosphorylation residue at 705 and a serine phosphorylation residue at 727. Red font represents activation PTM sites, blue font represents inactive PTM sites. B Left part, the canonical STAT3 signaling pathway is activated by multiple receptors including interleukin-6 (IL-6) and IL-6 family cytokines (IL-11, IL-23) receptors, G-coupled receptors (GPCRs), growth factor receptors and Toll-liker receptors which are stimulated by cognate ligands varies from cytokines, hormones, angiotensin, sphingosine-1-phosphate, and LPS et al. Traditionally, these receptors lack the intrinsic kinase activity. Once the ligands recognize the cognate receptors, the ligand-receptor shifts conformation and activate the JAKs, then provide the anchor site for STAT3 to bind via its SH2 domain. In addition to being activated by the membrane receptors, the constitutive activation of STAT3 is also induced by oncoproteins with tyrosine kinase activity like SRC and BCR-ABL. Two phosphorylated STAT3 form dimers via the phosphorylated tyrosine residue 705 of one monomer interacts with the SH2 domain of another monomer, the dimers subsequently translocate into the nucleus and bind to the specific DNA response elements in the promotor regions of the target genes which are involved in proliferation, metastasis, angiogenesis, tumor immune suppression, metabolic reprogramming, cancer stemness, drug resistance and exosome activity. Right part, the non-canonical STAT3 signaling pathway has three forms including mtSTAT3, unphosphorylated STAT3 and p-STAT3 Ser727 either alone or together with p-STAT3 Tyr705. These forms of STAT3 regulate the mitochondrial respiration, NF-κB, and other unknown genes are involved in activities. Created with BioRender.com

Fig. 2

STAT3 regulates immunosuppression and the crosstalk between tumor cells and immune cells in TME. Left panel, STAT3 activation induces the immunosuppression of innate immune, adaptive immune cells, as well as tumor-promoting activities of fibroblasts and endothelial cells. STAT3 activation promotes the expansion and proliferation of immunosuppressive MDSC and B cells, and drives the expansion and pro-tumor M2 polarization of immunosuppressive Treg cells and macrophage cells. Moreover, STAT3 activation simultaneously induces the expression of immune checkpoint molecules including PD-1, TIGIT and CTLA-4 in these cells. In addition, STAT3 activation impairs the immune-associated antitumor activities of neutrophils, CD8⁺ T cells and NK cells. STAT3 activation also suppresses the antitumor activity of dendritic cells via disrupting the maturation and antigen presentation. Purple fonts represent the innate immune cell subsets, orange fonts represent adaptive immune cell subsets. Red arrows represent tumor promoting function and blue arrows represent the decreasing antitumor function. Right panel, STAT3 regulates the crosstalk between tumor cells and immune cells in TME. Increasing STAT3 activities in tumor cells promotes the production of IL-6, IL-10, VEGF, TGFβ. STAT3 activation and these cytokines and factors mediated the expansion and polarization of MDSC and M2 macrophage. The increasing STAT3 activities diminish the maturation of dendritic cells which leads to the accumulation of Treg cells and thus blocks the antitumor activities of CD8⁺ T and NK cells. Created with BioRender.com

Fig. 3

STAT3 regulates the aerobic glycolysis, lipid metabolism, glutamine metabolism and energy production in tumor cells. The STAT3 activation regulates these metabolic reprogramming through the transcriptional regulation of genes involved in these processes, which contribute to multiple hallmarks of cancer including proliferation, immunosuppression, cancer stemness and drug resistance. Moreover, the mtSTAT3 accelerates ETC activity, decreases ROS production and MPTP opening, and promotes the calcium retention via binding to GRIM-19, which provides privileged advantages for the cancer progression. Created with BioRender.com

Fig. 4

Summary of STAT3 direct inhibitors and indirect inhibitors and the combination strategies. Upper panel, an overview of STAT3 direct inhibitors and indirect inhibitors. Lower panel, STAT3 inhibitors in combination with chemotherapy, radiotherapy, targeted therapy, immunotherapy, and dual-inhibiting of STAT3 mediate metabolic alteration of tumor cells and immune cells. Created with BioRender.com