The DNA Damage Response and Inflammation in Cancer

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting the demise of cells with unrepairable DNA lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR signaling can also favor tumor progression and resistance to therapy. Indeed, DDR signaling in cancer cells has been consistently linked to the inhibition of tumor-targeting immune responses. Here, we discuss the complex interactions between the DDR and inflammation in the context of oncogenesis, tumor progression, and response to therapy. Significance: Accumulating preclinical and clinical evidence indicates that DDR is intimately connected to the emission of immunomodulatory signals by normal and malignant cells, as part of a cell-extrinsic program to preserve organismal homeostasis. DDR-driven inflammation, however, can have diametri-cally opposed effects on tumor-targeting immunity. Understanding the links between the DDR and inflammation in normal and malignant cells may unlock novel immunotherapeutic paradigms to treat cancer.