Epigenetically suppressed tumor cell intrinsic STING promotes tumor immune escape

Zheng, Hui; Wu, Lizhen; Xiao, Qian; Meng, Xiangyu; Hafiz, Alex; Yan, Qin; Lu, Renquan; Cao, Jian

doi:10.1016/j.biopha.2022.114033

Cited by 14 publications

(5 citation statements)

References 37 publications

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“…Epigenetic silencing of STING and cGAS inhibited tumor cell death and anti-tumor response ( 126 ). STING knockout CT26 colon carcinoma cells significantly promoted tumor growth in immune-competent C57BL/6 mice and BALB/c mice compared to parent CT26 cells ( 122 ). CRC patients with high STING expression exhibited increased intratumoral CD8 + T cell infiltration and less frequent lymphovascular invasion in the early stage of cancer and had longer overall and recurrence-free survival compared to CRC patients with low STING expression ( 124 ), which has also been confirmed by Yang et al.…”

Section: The Cgas-sting Pathway In Colorectal Cancermentioning

confidence: 98%

cGAS-STING signaling pathway in intestinal homeostasis and diseases

Yang,

Wang,

Peugnet-González

et al. 2023

Front. Immunol.

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The intestinal mucosa is constantly exposed to commensal microbes, opportunistic pathogens, toxins, luminal components and other environmental stimuli. The intestinal mucosa consists of multiple differentiated cellular and extracellular components that form a critical barrier, but is also equipped for efficient absorption of nutrients. Combination of genetic susceptibility and environmental factors are known as critical components involved in the pathogenesis of intestinal diseases. The innate immune system plays a critical role in the recognition and elimination of potential threats by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This host defense is facilitated by pattern recognition receptors (PRRs), in which the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has gained attention due to its role in sensing host and foreign double-stranded DNA (dsDNA) as well as cyclic dinucleotides (CDNs) produced by bacteria. Upon binding with dsDNA, cGAS converts ATP and GTP to cyclic GMP-AMP (cGAMP), which binds to STING and activates TANK binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), inducing type I interferon (IFN) and nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokines, which have diverse effects on innate and adaptive immune cells and intestinal epithelial cells (IECs). However, opposite perspectives exist regarding the role of the cGAS-STING pathway in different intestinal diseases. Activation of cGAS-STING signaling is associated with worse clinical outcomes in inflammation-associated diseases, while it also plays a critical role in protection against tumorigenesis and certain infections. Therefore, understanding the context-dependent mechanisms of the cGAS-STING pathway in the physiopathology of the intestinal mucosa is crucial for developing therapeutic strategies targeting the cGAS-STING pathway. This review aims to provide insight into recent findings of the protective and detrimental roles of the cGAS-STING pathway in intestinal diseases.

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Section: The Cgas-sting Pathway In Colorectal Cancermentioning

confidence: 98%

cGAS-STING signaling pathway in intestinal homeostasis and diseases

Yang,

Wang,

Peugnet-González

et al. 2023

Front. Immunol.

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“…However, several of these mechanisms are suppressed in the TME during tumorigenesis 113 . For instance, hypoxia, 114 epigenetic modifications 115 and translational regulation 116 in the TME also can regulate immune escape and promote tumour development. Researchers have discovered that the dynamic interactions between the neoplastic cells and non‐neoplastic host components within the TME can affect carcinogenesis, 117 tumour metastasis, 118 cancer progression 119 and drug resistance of cancer cells 120 …”

Section: Pdtos In Immunotherapymentioning

confidence: 99%

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

Mei,

Liu,

Tian

et al. 2024

Clinical & Translational Med

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BackgroundOrganoid technology is an emerging and rapidly growing field that shows promise in studying organ development and screening therapeutic regimens. Although organoids have been proposed for a decade, concerns exist, including batch‐to‐batch variations, lack of the native microenvironment and clinical applicability.Main bodyThe concept of organoids has derived patient‐derived tumour organoids (PDTOs) for personalized drug screening and new drug discovery, mitigating the risks of medication misuse. The greater the similarity between the PDTOs and the primary tumours, the more influential the model will be. Recently, ‘tumour assembloids’ inspired by cell‐coculture technology have attracted attention to complement the current PDTO technology. High‐quality PDTOs must reassemble critical components, including multiple cell types, tumour matrix, paracrine factors, angiogenesis and microorganisms. This review begins with a brief overview of the history of organoids and PDTOs, followed by the current approaches for generating PDTOs and tumour assembloids. Personalized drug screening has been practised; however, it remains unclear whether PDTOs can predict immunotherapies, including immune drugs (e.g. immune checkpoint inhibitors) and immune cells (e.g. tumour‐infiltrating lymphocyte, T cell receptor‐engineered T cell and chimeric antigen receptor‐T cell). PDTOs, as cancer avatars of the patients, can be expanded and stored to form a biobank.ConclusionFundamental research and clinical trials are ongoing, and the intention is to use these models to replace animals. Pre‐clinical immunotherapy screening using PDTOs will be beneficial to cancer patients.Key Points The current PDTO models have not yet constructed key cellular and non‐cellular components. PDTOs should be expandable and editable. PDTOs are promising preclinical models for immunotherapy unless mature PDTOs can be established. PDTO biobanks with consensual standards are urgently needed.

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“…A close correlation has been observed between cGAS-STING signaling and methylation changes, particularly those involving histone lysine demethylase 5 (KDM5) 111 . Inhibitors of KDM5 activate STING expression in mouse colorectal cancer cells and inhibit tumor growth in a STING-dependent manner 112 . Falahat et al 113 , through whole-genome DNA methylation analysis, have discovered that hypermethylation of the promoter regions of cGAS and STING genes mediates their co-transcriptional silencing, thereby leading to widespread impairment of STING signaling in melanoma cells.…”

Section: Strategies For Harnessing the Cgas-sting Pathway In Cancer T...mentioning

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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Epigenetically suppressed tumor cell intrinsic STING promotes tumor immune escape

Cited by 14 publications

References 37 publications

cGAS-STING signaling pathway in intestinal homeostasis and diseases

cGAS-STING signaling pathway in intestinal homeostasis and diseases

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

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

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