Targeting STAT3 in Cancer Immunotherapy
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REVIEW
Open Access
Targeting STAT3 in Cancer Immunotherapy Sailan Zou1†, Qiyu Tong1†, Bowen Liu2, Wei Huang3, Yan Tian1* and Xianghui Fu1*
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: STAT3, Cancer, Immunosuppression, Immunotherapy, Immune checkpoint blockade, CAR-T
Introduction Dysregulation of immune checkpoints is a protective mechanism used by a number of malignancies to escape from the immune surveillance allowing for cancer development [1]. This has inspired the idea of boosting the host immune response as an anti-cancer therapy. Indeed, the blockage of immune checkpoints, including programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), improves clinical outcomes in subsets of patients with cancers previously considered to be essentially untreatable [2–4]. In order to expand the array of treatable cancers as well as increase the number of patients that respond to the therapy, novel therapeutic targets and new molecules/strategies should be urgently
* Correspondence: [email protected]; [email protected] † Sailan Zou and Qiyu Tong are co-first author. 1 Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China Full list of author information is available at the end of the article
identified and developed for immunotherapy appropriate for the clinical use. The signal transducer and activator of transcription (STAT) proteins are a family of cytoplasmic transcription factors which share an overall general structure, organized into functional modular domains. The mammalian STAT family comprises STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 that mediate multiple intracellular signaling pathways [5]. Among them, STAT3 is involved in numerous biological processes including cell proliferation, survival, differentiation, and angiog
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