Targeting DNA damage response to enhance cancer immunotherapy efficacy: molecular mechanisms and clinical advances.

The DNA damage response (DDR) is a critical cellular mechanism for maintaining genomic stability and integrity. Over the past decade, targeting DDR pathways in tumors has led to significant therapeutic advances but faces limitations such as drug resistance and combinatorial toxicity. Meanwhile, cancer immunotherapy has shown remarkable efficacy in some solid tumors, yet response rates to single-agent therapies remain modest and are often hindered by immunosuppression in the tumor microenvironment (TME). DDR inhibitors (DDRi) can potentiate antitumor immunity via mechanisms such as increased neoantigen release and activation of the cGAS-STING pathway, providing a rationale for combining DDRi with immunotherapy. Indeed, the combination of DDRi with immune checkpoint inhibitors (ICIs) has shown synergistic promise in clinical studies, while combinations of DDRi with novel immunotherapeutic approaches are now in early development. Here, we systematically review DDR-targeted cancer therapies and their molecular mechanisms for enhancing tumor immunogenicity, along with recent clinical advances in combining DDRi with immunotherapy. Our goal is to provide a theoretical foundation and translational insight for optimizing these combination strategies.