cGAS-STING Pathway as the Target of Immunotherapy for Lung Cancer

Dan, Qinfu; Yang, Yang; Ge, Hong

doi:10.2174/1568009623666221115095114

Cited by 6 publications

(2 citation statements)

References 83 publications

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“…In mouse models, ICB therapy eliminates tumor cells by T cell reactivation in the TME, dendritic cell authorization for T cell initiation and clonal expansion, and NK cell activation [ 9 ]. ‘Cold’ (“immune-desert”) tumors can be converted to ‘hot’ (“immunoinflammatory”) tumors with increased immune cell infiltration by remodeling the TME through activation of the STING pathway [ 10 ]. Reports indicate that the anti-tumor innate immune response interacts with the expression of other immune markers through the STING pathway, suggesting a potential therapy for recurrent NSCLC [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Role of STING in the treatment of non-small cell lung cancer

Tang,

Zhou,

et al. 2024

Cell Commun Signal

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Non-small cell lung cancer (NSCLC) is a prevalent form of lung cancer. Patients with advanced NSCLC are currently being treated with various therapies, including traditional radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. However, a considerable proportion of advance patients who cannot benefit from them. Consequently, it is essential to identify a novel research target that offers an encouraging perspective. The stimulator of interferon genes (STING) has emerged as such a target. At present, it is confirmed that activating STING in NSCLC tumor cells can impede the proliferation and metastasis of dormant tumor cells. This review focuses on the role of STING in NSCLC treatment and the factors influencing its activation. Additionally, it explores the correlation between STING activation and diverse therapy modalities for NSCLC, such as radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. Furthermore, it proposes the prospect of innovative therapy methods involving nanoparticles, with the aim of using the features of STING to develop more strategies for NSCLC therapy.

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Section: Introductionmentioning

confidence: 99%

Role of STING in the treatment of non-small cell lung cancer

Tang,

Zhou,

et al. 2024

Cell Commun Signal

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“…21,22 Interestingly, STK11 mut NSCLC has increased the availability of S-adenosylmethinione, which leads to epigenetic inactivation of the STING pathway. 23 Whether certain comutations can have a more activated STING pathway signature in STK11 mut NSCLC and enhance outcomes to ICIs in NSCLC is an area of active interest.…”

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confidence: 99%

Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non–Small-Cell Lung Cancer

Naqash,

Floudas,

Aber

et al. 2024

JCO Precis Oncol

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PURPOSE Non–small-cell lung cancer (NSCLC) with STK11mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs. PATIENTS AND METHODS NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11mut TP53mut versus STK11mut TP53wt NSCLC. RESULTS Overall, 12.6% of NSCLC tumors had a STK11mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11 mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53mut NSCLC ( P < .01). Compared with STK11mut TP53wt, tumors with STK11mut TP53mut had higher CD8+T cells and natural killer cells ( P < .01), higher TMB ( P < .001) and neoantigen load ( P < .001), and increased expression of MYC and HIF-1A ( P < .01), along with higher expression ( P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11mut TP53mut. In the DFCI cohort, compared with the STK11mut TP53wt cohort, the STK11mut TP53mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI. CONCLUSION STK11mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.

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Therapeutic targeting of cGAS–STING pathway in lung cancer

Wang,

Xing

2024

Cell Biology International

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The presence of DNA in the cytosol triggers a protective response from the innate immune system. Cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS–STING) is an essential cytosolic DNA sensor that triggers a potent innate immune response. As a result of this signaling cascade reaction, type I interferon and other immune mediators activate an immune response. The cGAS–STING pathway has great anticancer immunity‐boosting potential since it produces type I interferons. The detection of double‐stranded DNA (dsDNA) in response to various stimuli initiates a protective host's cGAS–STING signals. So, it is clear that a substantial relationship is expected between cancer biotherapy and the functioning of the cGAS–STING pathway. Several STING agonists with promising outcomes have been created for preclinical cancer therapy research. Notably, immunotherapy has dramatically extended patient survival and radically altered the course of lung cancer treatment, particularly in more advanced instances. However, this method is still ineffective for a large number of lung cancer patients. cGAS–STING can overcome resistance and boost anticancer immunity by stimulating the activity of many pro‐inflammatory mediators, augmenting dendritic cell cross‐presentation, and initiating a tumor‐specific CD8+ T cell response. This review aims to present the most recent results on the functionality of the cGAS–STING pathway in cancer progression and its potential as an immunotherapy target, with a focus on lung cancer.

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cGAS-STING Pathway as the Target of Immunotherapy for Lung Cancer

Cited by 6 publications

References 83 publications

Role of STING in the treatment of non-small cell lung cancer

Role of STING in the treatment of non-small cell lung cancer

Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non–Small-Cell Lung Cancer

Therapeutic targeting of cGAS–STING pathway in lung cancer

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