STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade

Yang, Hannah; Lee, Won Suk; Kong, So Jung; Kim, Chang Gon; Kim, Joo Hoon; Chang, Soo-Ho; Kim, Sewha; Kim, Gwangil; Chon, Hong Jae

doi:10.1172/jci125413

Cited by 202 publications

(224 citation statements)

References 46 publications

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“…256 Ubiquitination in the STING-dependent signaling pathway STING, an adapter transmembrane protein residing in the endoplasmic reticulum (ER), is an important innate immune sensor for tumor detection. [257][258][259] The STING pathway is activated by antigen-presenting cells (APCs) and produces type I IFNs. Subsequently, adequately activated APCs in the TME induce CD8 + T cell priming and lead to adaptive anticancer immune responses.…”

Section: Ubiquitination In Tumor Metabolism Regulationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

431

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Ubiquitination In Tumor Metabolism Regulationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

431

308

View full text Add to dashboard Cite

show abstract

“…Expression of the NK cellspecific ligand NKG2D retinoic acid early transcript 1 (RAE1) on cancer cells is highly up-regulated by STING once NK cells permeate into tumor tissue (231). The activation of STING in the endothelium within the tumor microenvironment (TME) could contribute to the remodeling of tumor vasculatures, and may have positive effects on tumor regression (232).…”

Section: Cgas-sting Pathway In Cancermentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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“…After viral infection, OVs continue self-replication until the cell bursts. (2) OVs can recruit and activate tumor-infiltrating immune cells by releasing a large amount of tumor antigens and secreting cytokines [ 2 , 8 , 22 ]. When an OV directly breaks tumor cells, viral antigens, tumor antigens, and damage-associated molecular patterns are massively released from dying tumor cells.…”

Section: Mechanism Of Ovs’ Anti-tumor Effectsmentioning

confidence: 99%

“…Immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4); programmed cell death 1 (PD-1); and PD-1’s main ligand PD-L1, have been introduced for the treatment of more than a dozen types of cancers [ 18 , 19 , 20 ]. However, only 20–30% of patients respond to ICI monotherapy, while others show intrinsic resistance to ICI treatment due to a non-inflamed cold tumor microenvironment (TME) [ 8 , 21 , 22 ]. These non-inflamed cold tumors are also described as “immune deserts” because they are poorly immunogenic and have very few anti-tumor immune effector cells within the TME [ 5 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

Chon

Kim

2020

IJMS

Self Cite

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Oncolytic virus (OV) is a new therapeutic strategy for cancer treatment. OVs can selectively infect and destroy cancer cells, and therefore act as an in situ cancer vaccine by releasing tumor-specific antigens. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype by stimulating widespread host immune responses against the tumor. Recent evidence suggests several possible applications of OVs against cancer, especially in combination with immune checkpoint inhibitors. In this review, we describe the molecular mechanisms of oncolytic virotherapy and OV-induced immune responses, provide a brief summary of recent preclinical and clinical updates on this rapidly evolving field, and discuss a combinational strategy that is able to overcome the limitations of OV-based monotherapy.

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STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade

Cited by 202 publications

References 46 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

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