The Development of STING Agonists and Emerging Results as a Cancer Immunotherapy

Hines, Jeremy T.; Kacew, Alec; Sweis, Randy F.

doi:10.1007/s11912-023-01361-0

Cited by 41 publications

(33 citation statements)

References 56 publications

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“…A major target for achieving this goal is the cGAS-STING pathway. While a number of STING agonists have entered clinical trials, [133] no cGAS agonist, apart from G3-ended Y-form Short DNA (G3-YSD), a canonical nucleic acid ligand, is available to date.…”

Section: Discussionmentioning

confidence: 99%

“…A major target for achieving this goal is the cGAS‐STING pathway. While a number of STING agonists have entered clinical trials, [ 133 ] no cGAS agonist, apart from G3‐ended Y‐form Short DNA (G3‐YSD), a canonical nucleic acid ligand, is available to date. Knowing the non‐canonical functions of cGAS and cGAMP, such compounds may have interesting properties and have distinct target and off‐target profiles as compared to STING agonists.…”

Section: Discussionmentioning

confidence: 99%

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Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

et al. 2023

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The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

et al. 2023

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“…Furthermore, the type I IFN signaling pathway promotes the intratumoral infiltration of CD8 + T-cells via C-X-C motif chemokine ligand 10 (CXCL10), which is induced by type I IFN ( Figure 2 ) [ 11 , 12 ]. Considering the importance of the cGAS–STING–type I IFN signaling pathway in cancer immunity, STING agonists are being developed [ 13 , 14 ]. Indeed, there are several ongoing clinical trials evaluating the efficacy of combination therapy using STING agonists in combination with anti-PD-1 antibodies on solid cancers, including melanoma [ 13 , 15 ].…”

Section: The Role Of Cgas and Sting In Immune Cells In The Tumor Micr...mentioning

confidence: 99%

“…Considering the importance of the cGAS–STING–type I IFN signaling pathway in cancer immunity, STING agonists are being developed [ 13 , 14 ]. Indeed, there are several ongoing clinical trials evaluating the efficacy of combination therapy using STING agonists in combination with anti-PD-1 antibodies on solid cancers, including melanoma [ 13 , 15 ]. In addition, recent studies have investigated whether there are existing therapies that can activate the cGAS–STING–type I IFN signaling pathway or increase the efficacy of STING agonists, with the following findings: By using melanoma, colon, and breast cancer mouse models and human cDC1 and cDC2 subsets from the peripheral blood, it was demonstrated that radiation therapy destroys tumor cells, which then release their dsDNA into the tumor microenvironment; cDC1 and cDC2 take up the dsDNA into their own cytoplasm.…”

Section: The Role Of Cgas and Sting In Immune Cells In The Tumor Micr...mentioning

confidence: 99%

“…To overcome these challenges, a non-CDN small molecule STING agonist, GSK3745417 (diABZI), that is systemically administered, has been developed [ 32 ]. As it showed efficacy for treating a colon cancer mouse model [ 32 ], diABZI in combination with anti-PD-1 Ab has undergone clinical trials for advanced solid tumors (NCT03843359) [ 13 ]. However, there are two major concerns [ 33 ]: Firstly, systemic STING activation may lead to severe toxicity due to the enhanced activation of type I IFN signaling and IL-6 signaling in off-target tissues.…”

Section: Sting Agonists In Clinical Trials and Next-generation Sting ...mentioning

confidence: 99%

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Immune Regulation by Cytosolic DNA Sensors in the Tumor Microenvironment

Fukuda

2023

Cancers

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cGAS and AIM2 are CDSs that are activated in the presence of cytosolic dsDNA and are expressed in various cell types, including immune and tumor cells. The recognition of tumor-derived dsDNA by CDSs in the cytosol of tumor-infiltrating dendritic cells (TIDCs) activates the innate and acquired immunity, thereby enhancing anti-tumor immune responses. STING is the downstream signaling effector of cGAS that induces type I interferon (IFN) signaling. Owing to their ability to activate TIDCs, STING agonists have been intratumorally injected in several clinical trials to enhance the anti-tumor immune response elicited by immune checkpoint antibodies. However, they have shown minimal effect, suggesting the importance of optimizing the dose and route of administration for STING agonists and deciphering other immune pathways that contribute to anti-tumor immune responses. Recent studies have revealed that AIM2 activity induces pro-tumor growth through multiple parallel pathways, including inhibition of STING-type I IFN signaling. Thus, AIM2 could be a potential molecular target for cancer immunotherapies. This review summarizes the current research on the roles of cGAS, STING, and AIM2 in immune cells and tumor cells in the tumor microenvironment and discusses the future prospects of anti-tumor treatment approaches based on these molecules.

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Biomaterial‐Based Therapeutic Delivery of Immune Cells

Dravid,

Singh,

García

2024

Adv Healthcare Materials

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Immune cell therapy is a transformative approach used to treat a wide range of diseases including type 1 diabetes, sickle cell disease, disorders of the hematopoietic system, and certain forms of cancers. Despite excellent clinical successes, the scope of adoptively transferred immune cells is limited because of toxicities like cytokine release syndrome and immune effector cell‐associated neurotoxicity in patients. Furthermore, reports suggest that such treatment can impact major organ systems including cardiac, renal, pulmonary, and hepatic systems in the long term. Additionally, adoptively transferred immune cells cannot achieve significant penetration into solid tissues, thus limiting their therapeutic potential. Recent studies suggest that biomaterial‐assisted delivery of immune cells can address these challenges by reducing toxicity, improving localization, and maintaining desired phenotypes to eventually regain tissue function. In this review, we highlight recent efforts in the field of biomaterial‐based immune cell delivery for the treatment of diseases, their pros and cons, and where these approaches stand in terms of clinical treatment.This article is protected by copyright. All rights reserved

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The Development of STING Agonists and Emerging Results as a Cancer Immunotherapy

Cited by 41 publications

References 56 publications

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

Immune Regulation by Cytosolic DNA Sensors in the Tumor Microenvironment

Biomaterial‐Based Therapeutic Delivery of Immune Cells

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