Harnessing the cooperation between DNA-PK and cGAS in cancer therapies: The cooperation between DNA-PK and cGAS
Clara Taffoni1, Moritz Schüssler1, Isabelle K Vila1
1IGMM, Université de Montpellier, CNRS, Montpellier, France.
Abstract:
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is central for the initiation of anti-tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS-STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA-dependent protein kinase (DNA-PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA-PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non-canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.
Insights
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway impacts cancer immunity. Understanding cGAS and DNA-PK regulation is crucial for predicting treatment efficacy and boosting anti-tumour responses.
Area of Science:
- Immunology
- Oncology
Background:
- The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is critical for initiating anti-tumour immune responses.
- STING agonists are extensively studied to enhance tumour immunogenicity, but the cGAS-STING axis can also promote tumourigenesis in some cases.
Purpose of the Study:
- To review recent findings on cGAS expression and activity regulation.
- To highlight the role of the DNA-dependent protein kinase (DNA-PK) complex in tumour cell inflammatory responses.
- To explore non-canonical functions of cGAS and cyclic GMP-AMP (cGAMP) in tumourigenesis.
Main Methods:
- Literature review of recent findings on cGAS-STING pathway regulation.
- Focus on DNA-PK complex as a novel activator of inflammatory responses in tumour cells.
- Analysis of non-canonical functions of cGAS and cGAMP.
Main Results:
- Recent findings illuminate the complex regulation of cGAS expression and activity.
- DNA-PK has emerged as a key activator of inflammatory responses within tumour cells.
- Non-canonical roles of cGAS and cGAMP in influencing tumourigenesis are identified.
Conclusions:
- Stratification analyses of cGAS and DNA-PK expression/activation status are proposed for predicting treatment efficacy.
- Considering these parameters concertedly is essential for developing effective strategies to enhance anti-tumour immunity.
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