Targeting DNA damage response and repair genes to enhance anticancer immunotherapy: rationale and clinical...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• DNA damage response and repair (DDR) genes are crucial for maintaining genomic integrity in replicating cells.
• DNA damage, whether from external factors or DDR gene deficiencies, significantly impacts tumor immunogenicity and boosts antitumor immune responses via neoantigen-dependent and independent pathways.
• Inhibition of DDR pathways is an established therapeutic strategy in various cancers.

Purpose of the Study:

• To review the rationale and potential of combining DDR inhibitors with immune checkpoint inhibitors.
• To explore how this combination strategy can enhance antitumor immune responses by inducing and amplifying DNA damage in cancer cells.

Main Methods:

• Literature review of studies investigating DNA damage response, repair mechanisms, and immunogenic effects of DNA damage.
• Analysis of preclinical and clinical data on DDR inhibitors and immune checkpoint inhibitors.
• Exploration of the synergistic potential between DDR inhibition and immune checkpoint blockade.

Main Results:

• DNA damage induced by DDR inhibition can enhance tumor immunogenicity and immune cell infiltration.
• Combining DDR inhibitors with immune checkpoint inhibitors may lead to amplified DNA damage and a more robust antitumor immune response.
• This combination strategy holds potential for overcoming resistance and improving treatment outcomes in metastatic cancers.

Conclusions:

• The combination of DDR inhibitors and immune checkpoint inhibitors represents a promising therapeutic strategy.
• Exploiting DNA damage to enhance antitumor immunity offers a novel approach to cancer treatment.
• Further research and clinical trials are warranted to validate the efficacy and safety of this combined therapeutic approach.