STING activation in cancer immunotherapy

Su, Ting; Zhang, Yu; Valerie, Kristoffer; Wang, Xiangyang; Lin, Shuibin; Zhu, Guizhi

doi:10.7150/thno.37574

Cited by 169 publications

(138 citation statements)

References 93 publications

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“…Over the past few years, these observations prompted an intense wave of investigation aimed at the identification and development of pharmacological STING agonists for use in cancer patients. 9,68,91,92 Historically, flavone acetic acid (FAA) has been the first of such molecules to be investigated for its anticancer properties, although FAA was not known to trigger STING activation at that time. 93 Indeed, FAA was originally characterized as a vascular-disrupting agent that showed some antitumoral activity against murine colon tumors.…”

Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

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Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

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Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

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“…Recently studies demonstrated that STING pathway had tremendous potential for immunotherapy from bench to bedside (24,(45)(46)(47). However, whether STING pathway involved in neuropathic pain process and whether STING pathway regulate ER-phagy process still remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine versus ketamine in attenuating neuropathic pain through modulating STING/TBK pathway to modulate spinal ER-phagy in neuropathic pain model

Liu

Ding

Wang

et al. 2020

Preprint

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Background: Our previous studies suggested that stimulator of interferon genes (STING) level was altered in medial prefrontal cortex (mPFC) of spinal nerve ligation (SNL) rats. Methods:In this study, we investigated that whether dexmedetomidine and ketamine provide antianxiety and anti-nociceptive effects via modulating spinal STING/TBK pathway to alter ER-phagy in SNL rats. We evaluated the analgesia and antianxiety effects of ketamine and dexmedetomidine in SNL rats. 2'3'-cGAMP (STING pathway agonist) was administrated to investigate whether enhanced spinal STING pathway could reverse dexmedetomidine or ketamine treatment effects in SNL rats respectively. Analgesia effects were measured with mechanical withdrawal threshold (MWT) and antianxiety effect was measured with open field test (OFT). Proteins expression levels were evaluated by Western blotting. Distribution and cellular localization of STING pathway and ER stress were evaluated by confocal immunofluorescence.Results: SNL induced mechanical hypersensitivity and anxiety; STING pathway was involved in the modulation of ER stress and ER-phagy in SNL rats; Dexmedetomidine and ketamine provided analgesia and antianxiety effects in SNL rats; Dexmedetomidine and ketamine alleviated ER stress via inhibiting STING pathway to enhance ER-phagy in SNL rats. Conclusions:In all, both ketamine and dexmedetomidine provided antianxiety and anti-nociceptive effects through alleviating ER stress via inhibiting STING/TBK pathway to modulate spinal ER-phagy in SNL rats.

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“…Li et al synthesised a 2′3′-cGAMP analogue, 2′3′-cG S A S MP, which was resistant to ENPP1 hydrolysis and showed similar affinity for hSTING in vitro as well as ten-fold more potent induction of IFN-β secretion from THP-1 cells. This bisphosphothioate analogue was also ~40 times more resistant to ENPP1 hydrolysis than the naturally occurring ligand, rendering it a desirable compound for future development [ 15 , 79 ]. Gajewski et al synthesised various synthetic CDN-derivatives and selected those which displayed binding affinity for all hSTING alleles while retaining the ability to bind mSTING [ 20 ].…”

Section: Sting Activating Drugsmentioning

confidence: 99%

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Aval

Pease

Sharma

et al. 2020

JCM

154

130

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Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

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STING activation in cancer immunotherapy

Cited by 169 publications

References 93 publications

Trial watch: STING agonists in cancer therapy

Trial watch: STING agonists in cancer therapy

Dexmedetomidine versus ketamine in attenuating neuropathic pain through modulating STING/TBK pathway to modulate spinal ER-phagy in neuropathic pain model

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

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