cGAS-STING pathway in cancer biotherapy
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cGAS-STING pathway in cancer biotherapy Yang Wang† , Jingwen Luo† , Aqu Alu , Xuejiao Han , Yuquan Wei
and Xiawei Wei*
Abstract The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGASSTING agonists, related clinical trials and agonist delivery systems. Keywords: cGAS-STING pathway, Cancer biotherapy, Interferon, Cyclic dinucleotide, Agonist, Delivery system, Clinical trials
Introduction Cancer biotherapy replies on stimulating the body’s antitumor biological response by initiating the host’s defensive mechanisms and using biological agents. By killing cancer cells and inhibiting its growth, cancer treatment is to regulate the balance between immune responses and tumors to treat cancer, whose mechanism is different from that of chemotherapy, radiotherapy and surgery [1, 2]. Current cancer biotherapy includes cancer vaccine [3], cancer immunotherapy [4], cancer gene therapy [5] and antiangiogenesis therapy [6]. In the early years, the therapeutic effect was witnessed in tumors with strong immunogenicity, especially melanoma [7]. But now, cancer biotherapy research has been spread into breast cancer [8], lung cancer [9] and liver cancer [10]. Meanwhile, anti-neovascularization drugs, monoclonal antibodies, cancer vaccines, gene therapy drugs and immunomodulators have been used clinically and been studied in clinical trials. * Correspondence: [email protected] † Yang Wang and Jingwen Luo contributed equally to this work. Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China
Tumor immune surveillance is illustrated as the immune system’s recognition and the elimination of malignancies. Once tumor-associated antigens are perceived, innate immunity, adaptive immunity and cytokines function together to fight against tumors [11]. In long-term coexistence of the immune system and cancer cells, tumors alter tumor-associated antigens to directly escape
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