ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade

Liu, Xiaolan; Cen, Xufeng; Wu, Ronghai; Chen, Ziyan; Xie, Yaoqin; Wang, Fengqi; Shan, Bing; Zeng, Ling‐Hui; Zhou, Jichun; Xie, Bojian; Cai, Yangjun; Jy, Huang; Liang, Yingjiqiong; Wu, Youqian; Zhang, Chao; Wang, Dongrui; Xia, Hong

doi:10.1038/s41467-023-39920-5

Cited by 11 publications

(7 citation statements)

References 45 publications

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“…Therefore, candidate compounds should be carefully selected and validated. To be noted, the validation rate for miR-132 inducers was comparable to other recently published small compound screens [60][61][62] .…”

Section: Discussionsupporting

confidence: 64%

Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing

Nguyen,

Wei,

Silva

et al. 2023

Nat Commun

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MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer’s disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.

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Section: Discussionsupporting

confidence: 64%

Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing

Nguyen,

Wei,

Silva

et al. 2023

Nat Commun

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“… 217 STING agonists have also been found to sensitize tumors to immune checkpoint inhibitors. 218 This discovery suggests a synergistic potential where activating the STING pathway can enhance the effectiveness of treatments that target immune checkpoints.…”

Section: Innate Immune Pathways In Cancermentioning

confidence: 99%

“… 371 , 372 Additionally, the effectiveness of ICBs depends on the sufficient expression of corresponding receptors on target cells, and innate immune pathway agonists can upregulate the expression of these molecules. 218 , 220 , 499 , 524 …”

Section: Cancer Therapeutic Strategies Targeting Innate Immune Pathwaymentioning

confidence: 99%

Harnessing innate immune pathways for therapeutic advancement in cancer

Hu,

Sun,

Lin

et al. 2024

Sig Transduct Target Ther

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The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor’s innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

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“…Moreover, Bruand et al 51 have revealed that the elimination of endogenous STING in tumors decreases neoangiogenesis, augments CD8 + T cell infiltration, and reverses resistance to dual immune checkpoint blockade therapy. Ariadne RBR E3 ubiquitin protein ligase 1 (Arih1) mediates the ubiquitination and degradation of DNA PKcs, and consequently triggers STING pathway activation, promotes the infiltration of cytotoxic T cells, inhibits tumor growth, and renders tumors sensitive to PD-L1 blockade 52 . The nuclear receptor Rev-erb alpha (NR1D1) fosters the accumulation of cytoplasmic DNA fragments induced by DNA damage, and subsequently activates the cGAS-STING signaling pathway.…”

Section: The Cgas-sting Pathway In Cancer Biologymentioning

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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ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade

Cited by 11 publications

References 45 publications

Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing

Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing

Harnessing innate immune pathways for therapeutic advancement in cancer

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

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