Strategies involving STING pathway activation for cancer immunotherapy: Mechanism and agonists

Pan, Xiaohui; Zhang, Wenxin; Guo, Hongjie; Wang, Longsheng; Wu, Honghai; Ding, Ling; Yang, Bo

doi:10.1016/j.bcp.2023.115596

Cited by 11 publications

(4 citation statements)

References 147 publications

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“…STING agonists and antagonists (Figure 6) have been extensively reviewed [178][179][180][181][182][183][184], so here we only emphasize that the development of these small molecules is challenging by the relatively large size of the 700-Da binding pocket in the STING molecule and differences between mouse and human STINGs. Also, it is difficult to minimize side effects such as excessive stress in T cells, which can lead to cytokine storms, apoptosis of cancer-associated cells instead of IFN secretion, or induction of the tolerogenic enzyme IDO (indoleamine-2,3-dioxygenase).…”

Section: Pharmaceutical Achievements In the Regulation Of The Cgas-st...mentioning

confidence: 99%

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

Korneenko,

Pestov,

Nevzorov

et al. 2023

Pharmaceuticals

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The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

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Section: Pharmaceutical Achievements In the Regulation Of The Cgas-st...mentioning

confidence: 99%

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

Korneenko,

Pestov,

Nevzorov

et al. 2023

Pharmaceuticals

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“…As a protein localized on the ER membrane, the stimulator of interferon genes (STING) plays a vital role in activating immune responses [116,117]. Cyclic GMP-AMP synthase (cGAS) is a cellular DNA sensor that could recognize pathogen-released cytoplasmic double-stranded DNA (dsDNA).…”

Section: Cytokinesmentioning

confidence: 99%

Innate Immunity in Cancer Biology and Therapy

Zhang

Xue

et al. 2023

IJMS

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Immunotherapies including adaptive immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells, have developed the treatment of cancer in clinic, and most of them focus on activating T cell immunity. Although these strategies have obtained unprecedented clinical responses, only limited subsets of cancer patients could receive long-term benefits, highlighting the demand for identifying novel targets for the new era of tumor immunotherapy. Innate immunity has been demonstrated to play a determinative role in the tumor microenvironment (TME) and influence the clinical outcomes of tumor patients. A thorough comprehension of the innate immune cells that infiltrate tumors would allow for the development of new therapeutics. In this review, we outline the role and mechanism of innate immunity in TME. Moreover, we discuss innate immunity-based cancer immunotherapy in basic and clinical studies. Finally, we summarize the challenges in sufficiently motivating innate immune responses and the corresponding strategies and measures to improve anti-tumor efficacy. This review could aid the comprehension of innate immunity and inspire the creation of brand-new immunotherapies for the treatment of cancer.

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“…Activation of the cGAS-STING pathway has shown favorable tumor regression effects in clinical models, by evoking systemic anti-tumor responses, particularly when combined with immune checkpoint inhibitors (ICIs). These combination therapies have achieved remarkable improvements in survival rates in phase I clinical trials 6 , 7 . Consequently, STING pathway activation is considered a means of increasing tumor immunotherapy efficacy through mobilizing both innate and adaptive immune mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

Zhang,

Yu,

Peng

et al. 2024

Cancer Biol Med

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The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment. Within this landscape, the innate immune system, a critical sentinel protecting against tumor incursion, is a key player. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway has been found to be a linchpin of innate immunity: activation of this signaling pathway orchestrates the production of type I interferon (IFN-α/β), thus fostering the maturation, differentiation, and mobilization of immune effectors in the tumor microenvironment. Furthermore, STING activation facilitates the release and presentation of tumor antigens, and therefore is an attractive target for cancer immunotherapy. Current strategies to activate the STING pathway, including use of pharmacological agonists, have made substantial advancements, particularly when combined with immune checkpoint inhibitors. These approaches have shown promise in preclinical and clinical settings, by enhancing patient survival rates. This review describes the evolving understanding of the cGAS-STING pathway’s involvement in tumor biology and therapy. Moreover, this review explores classical and non-classical STING agonists, providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies. Despite challenges and complexities, the cGAS-STING pathway, a promising avenue for enhancing cancer treatment efficacy, has the potential to revolutionize patient outcomes.

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Strategies involving STING pathway activation for cancer immunotherapy: Mechanism and agonists

Cited by 11 publications

References 147 publications

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

Innate Immunity in Cancer Biology and Therapy

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

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