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Updated: Nov 8, 2025
Monitoring the Cancer-Immunity Cycle and Exploring Tumor Microenvironment Dynamics
Published on: June 7, 2024
Interfaces between cellular responses to DNA damage and cancer immunotherapy
Domenic Pilger1, Leonard W Seymour2, Stephen P Jackson1
1Wellcome Trust/Cancer Research UK Gurdon Institute, Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, United Kingdom.
Abstract:
The DNA damage response (DDR) fulfils essential roles to preserve genome integrity. Targeting the DDR in tumors has had remarkable success over the last decade, exemplified by the licensing of PARP inhibitors for cancer therapy. Recent studies suggest that the application of DDR inhibitors impacts on cellular innate and adaptive immune responses, wherein key DNA repair factors have roles in limiting chronic inflammatory signaling. Antitumor immunity plays an emerging part in cancer therapy, and extensive efforts have led to the development of immune checkpoint inhibitors overcoming immune suppressive signals in tumors. Here, we review the current understanding of the molecular mechanisms underlying DNA damage-triggered immune responses, including cytosolic DNA sensing via the cGAS/STING pathway. We highlight the implications of DDR components for therapeutic outcomes of immune checkpoint inhibitors or their use as biomarkers. Finally, we discuss the rationale for novel combinations of DDR inhibitors with antagonists of immune checkpoints and current hindrances limiting their broader therapeutic applications.
Insights
Targeting DNA damage response (DDR) pathways can enhance cancer immunotherapy. DDR inhibitors influence immune responses and may improve outcomes for immune checkpoint inhibitors, offering new therapeutic strategies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The DNA damage response (DDR) is crucial for maintaining genome stability.
- Targeting DDR pathways, such as with PARP inhibitors, has shown success in cancer therapy.
- Emerging evidence links DDR to innate and adaptive immune responses in tumors.
Purpose of the Study:
- To review the molecular mechanisms of DNA damage-triggered immune responses.
- To highlight the role of DDR components in the efficacy of immune checkpoint inhibitors (ICIs).
- To discuss the potential of combining DDR inhibitors with ICIs.
Main Methods:
- Literature review of studies on DDR, cancer immunity, and immunotherapy.
- Analysis of molecular pathways linking DNA damage sensing (e.g., cGAS/STING) to immune signaling.
- Evaluation of clinical implications and therapeutic strategies.
Main Results:
- DDR factors can modulate chronic inflammatory signaling and influence antitumor immunity.
- DDR components may serve as biomarkers for ICI therapy response.
- DDR inhibitors can impact the tumor microenvironment and immune cell function.
Conclusions:
- Understanding DDR-immune interactions is key for optimizing cancer therapy.
- Combining DDR inhibitors with ICIs presents a promising therapeutic avenue.
- Further research is needed to overcome hindrances for broader clinical application of these combinations.
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