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DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of
Meng-Jie Wang1,2, Yu Xia3,4, Qing-Lei Gao5,6
1Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.
Insights
DNA damage impacts tumor development and the immune microenvironment. Understanding DNA damage response and cytokines is crucial for developing effective cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- DNA damage is a fundamental process in tumorigenesis and tumor progression.
- Tumor-intrinsic DNA damage can trigger cellular stress responses that shape the tumor immune microenvironment (TIME).
- Key signaling pathways like cGAS-STING and ATM/ATR are activated by DNA damage, influencing cytokine secretion.
Purpose of the Study:
- To comprehensively review the intricate relationship between DNA damage response and cytokines within tumors.
- To elucidate the dual immunoregulatory roles of these cytokines in the tumor immune microenvironment.
- To summarize current clinical trials targeting DNA damage-related pathways and cytokines and offer future perspectives.
Main Methods:
- Literature review of studies on DNA damage, cytokines, and the tumor immune microenvironment.
- Analysis of signaling pathways activated by DNA damage, including cGAS-STING and ATM/ATR.
- Compilation of data from clinical trials investigating targeted therapies.
Main Results:
- DNA damage significantly influences the tumor immune microenvironment through stress responses and cytokine signaling.
- Activated pathways like cGAS-STING and ATM/ATR mediate the secretion of diverse cytokines with varied immune functions.
- Cytokines exhibit dual roles in regulating anti-tumor immunity, impacting therapeutic strategies.
Conclusions:
- A deeper understanding of how DNA damage and cytokines reshape the TIME is essential for advancing cancer therapy.
- Targeting DNA damage response pathways and associated cytokines holds promise for novel immunotherapeutic approaches.
- Emerging technologies may offer new avenues for exploiting the DNA damage-cytokine axis in cancer treatment.
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