Combination of STING agonist and CXCR3 antagonist disrupts immune tolerance to overcome anti-PD-L1 resistance in lung adenocarcinoma under oxidative stress

Zhu, Lingling; Gao, Honglin; Huang, Shiqi; Cao, Ting; Zhai, Xiaoyu; Hu, Jia; Wang, Ting; Dong, Jingsi; Liu, Zelong; Jiang, Chen; Liu, Jiewei; Zhang, Zhirong; Zhou, Qinghua

doi:10.1016/j.gene.2022.146962

Cited by 3 publications

(2 citation statements)

References 43 publications

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“…However, the functions of BMS1166 might be secondary to other non-specific toxic effects 67 . A recent study identifies that activation of STING facilitates overcoming anti-PD-L1 resistance 68 . The drug combination study further supported that targeted activation of STING enhances the efficacy of PD-L1 blockade in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma

Cai,

Chen,

et al. 2023

Int. J. Biol. Sci.

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Genomic instability is a significant driver of cancer. As the sensor of cytosolic DNA, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in regulating anti-tumor immunity and cell death. However, the role and regulatory mechanisms of STING in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we reported that sterile alpha motif and HD domain-containing protein 1 (SAMHD1) deficiency induced STING expression and inhibited tumor growth in DLBCL. High level of SAMHD1 was associated with poor prognosis in DLBCL patients. Down-regulation of SAMHD1 inhibited DLBCL cell proliferation both in vitro and in vivo . Moreover, we found that SAMHD1 deficiency induced DNA damage and promoted the expression of DNA damage adaptor STING. STING overexpression promoted the formation of Caspase 8/RIPK3/ASC, further leading to MLKL phosphorylation, Caspase 3 cleavage, and GSDME cleavage. Up-regulation of necroptotic, apoptotic, and pyroptotic effectors indicated STING-mediated PANoptosis. Finally, we demonstrated that the STING agonist, DMXAA, enhanced the efficacy of a PD-L1 inhibitor in DLBCL. Our findings highlight the important role of STING-mediated PANoptosis in restricting DLBCL progression and provide a potential strategy for enhancing the efficacy of immune checkpoint inhibitor agents in DLBCL.

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Section: Discussionmentioning

confidence: 99%

Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma

Cai,

Chen,

et al. 2023

Int. J. Biol. Sci.

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“…For instance, a combination of STING agonist and CXCR3 antagonist was reported to overcome anti- PD-L1 resistance in lung adenocarcinoma under oxidative stress. 239 And a combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101 can effectively overcome immunotherapy resistance in immune-excluded and immune-desert models. 240 In addition, a methoxy poly(ethylene glycol) (mPEG)-masked CD44×PD-L1/CD3 trispecific T-cell nanoengager was loaded with the STING agonist can transform the cold tumor into a hot tumor and eradicate the large established triplenegative breast cancer.…”

Section: Sting-related Targeted Therapiesmentioning

confidence: 99%

Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy

Zhang

Zhou

Ouyang

et al. 2022

Sig Transduct Target Ther

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Since the discovery of Stimulator of Interferon Genes (STING) as an important pivot for cytosolic DNA sensation and interferon (IFN) induction, intensive efforts have been endeavored to clarify the molecular mechanism of its activation, its physiological function as a ubiquitously expressed protein, and to explore its potential as a therapeutic target in a wide range of immune-related diseases. With its orthodox ligand 2’3’-cyclic GMP–AMP (2’3’-cGAMP) and the upstream sensor 2’3’-cGAMP synthase (cGAS) to be found, STING acquires its central functionality in the best-studied signaling cascade, namely the cGAS–STING–IFN pathway. However, recently updated research through structural research, genetic screening, and biochemical assay greatly extends the current knowledge of STING biology. A second ligand pocket was recently discovered in the transmembrane domain for a synthetic agonist. On its downstream outputs, accumulating studies sketch primordial and multifaceted roles of STING beyond its cytokine-inducing function, such as autophagy, cell death, metabolic modulation, endoplasmic reticulum (ER) stress, and RNA virus restriction. Furthermore, with the expansion of the STING interactome, the details of STING trafficking also get clearer. After retrospecting the brief history of viral interference and the milestone events since the discovery of STING, we present a vivid panorama of STING biology taking into account the details of the biochemical assay and structural information, especially its versatile outputs and functions beyond IFN induction. We also summarize the roles of STING in the pathogenesis of various diseases and highlight the development of small-molecular compounds targeting STING for disease treatment in combination with the latest research. Finally, we discuss the open questions imperative to answer.

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Targeting activation of cGAS-STING signaling pathway by engineered biomaterials for enhancing cancer immunotherapy

Liang,

Jin,

Deng

et al. 2024

Materials Today

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Combination of STING agonist and CXCR3 antagonist disrupts immune tolerance to overcome anti-PD-L1 resistance in lung adenocarcinoma under oxidative stress

Cited by 3 publications

References 43 publications

Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma

Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma

Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy

Targeting activation of cGAS-STING signaling pathway by engineered biomaterials for enhancing cancer immunotherapy

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