The DNA damage response and cancer immunotherapy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• The DNA damage response (DDR) and immune system are crucial for genomic integrity and host defense.
• Their interplay is increasingly recognized as vital for cancer immunotherapy efficacy.

Purpose of the Study:

• To review the molecular mechanisms linking DDR defects to enhanced immunotherapy response.
• To discuss advances in DDR-targeted combination strategies and resistance mechanisms.

Main Methods:

• Literature review of emerging research on DDR and cancer immunotherapy.
• Analysis of molecular pathways involving genomic instability, neoantigens, and the cGAS-STING pathway.
• Examination of clinical implications and therapeutic strategies.

Main Results:

• DDR-deficient tumors or those treated with DDR inhibitors exhibit genomic instability, producing neoantigens and cytosolic DNA.
• This stimulates the cGAS-STING pathway, increasing type I interferon and immune cell recruitment.
• These effects synergize to improve responsiveness to immune checkpoint blockade.

Conclusions:

• Exploiting DDR deficiencies offers a promising strategy to potentiate cancer immunotherapy.
• DDR-targeted combination therapies and overcoming resistance are key to improving treatment outcomes.