Targeting STAT3 in Cancer Immunotherapy

Abstract

As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

Keywords: CAR-T; Cancer; Immune checkpoint blockade; Immunosuppression; Immunotherapy; STAT3.

Fig. 1

The domain structure and signaling pathway of STAT3. a Schematic domain structure of STAT3. STAT3 is characterized by the presence of six different functional domains, including an amino-terminal domain (NTD) for cooperative binding of STAT proteins to multiple consensus DNA sites, a coiled-coil domain (CCD) for recruitment of STAT3 to the receptor as well as subsequent phosphorylation, dimerization and nuclear translocation, a DNA-binding domain (DBD) for recognizing and binding to a specific consensus DNA sequence, a linker domain for connecting the DBD with the SRC homology 2 (SH2) domain, a SH2 domain for recruitment and activation as well as dimerization of the STAT3 molecule by interacting with phosphorylated tyrosine residues in the opposing subunit, and a carboxyl-terminal transactivation domain (TAD). b STAT3 signaling pathway. STAT3 is activated by upstream growth factor kinases and cytokine receptors. Non-receptor tyrosine kinases such as SRC and ABL can also lead to constitutive activation of STAT3. Phosphorylated STAT3 dimerizes and translocates to nucleus, which causes the transcription of target genes including immunosuppression, angiogenesis, metastasis, proliferation and survival. The signaling pathway can be inhibited by SOCS proteins, PIAS proteins, and protein tyrosine phosphatases (PTPases), etc. c Interplay between noncoding RNAs and STAT3 signaling pathway. On the one hand, miRNAs and lncRNAs can regulate STAT3 activation through not only directly targeting STAT3, but also targeting the components of the STAT3 signaling pathway, such as IL-6, JAK2, SOCS1 and PIAS3; CircRNAs usually regulate STAT3 by acting as sponges for miRNAs. On the other hand, STAT3 is able to regulate miRNAs and lncRNAs expression in many ways.

Fig. 2

STAT3 induces the immunosuppression in the TME. STAT3 activity in tumor cells supports multiple hallmarks of cancer, including increased secretion of immunosuppressive factors such as IL-6, IL-10 and EGFR, which can activate STAT3 in the innate and adaptive immune cell subsets as well as CAFs in the TME. Likewise, immune cells and CAFs within the TME can release certain factors including IL-6, which subsequently enhance STAT3 signaling in tumor cells. Elevated STAT3 in the TME has dual effects. On the one hand, STAT3 favors the accumulation and enrichment of immunosuppressive Treg cells and B cells, as well as the polarization of M2-like macrophages, which instigate immune evasion. Particularly, STAT3 is a major driver for increased expression of immune checkpoint molecules (such as PD-L1, PD-L2 and CTLA-4) in these cells. On the other hand, STAT3 in CD8⁺ T cells, NK cells and neutrophils evokes restrained anti-tumor cytolytic activities. STAT3 can also inhibit the anti-tumor ability of DCs through dampening their maturation, activation and antigen presentation. Besides, STAT3 in CAFs can promote their proliferation, survival and migration, and drive the remodeling of tumor stroma for tumor progression. Collectively, STAT3 induces the immunosuppression in the TME, thereby promoting tumor progression with diminishing the anti-tumor immunity.

Fig. 3

Targeting STAT3 in combination cancer immunotherapy. a Summary of the key steps in the development of STAT3-targeting therapeutics. The first step in the development of STAT3-targeting therapeutics involves the systematic selection of STAT3 inhibitors (including direct or indirect inhibitors) and STAT3 inhibitors-based combined immunotherapy, and then elucidating the biology and effects of these candidates to cancer using tumor cell lines and patient samples. The next major challenge involves the in vivo model-based validation that these therapeutic candidates must undergo rigorous disease-specific in vivo testing using rodents and non-human primate models. Key challenges in translating STAT3 inhibitors into the clinic are low bioavailability and the lack of specific targeting of the tumor site. b Targeting STAT3 in combination cancer immunotherapy. Targeting STAT3 in combination cancer immunotherapy can not only enhance the anti-tumor effects, but also reduce drug resistance. Besides, combined STAT3 inhibitors with CAR-T cells can reduce excessive expansion of CAR-T cells and alleviate cytokine release syndrome (CRS), resulting in lower occurrence of immune-related adverse effects.