DNA-damage response (DDR) is a complex signaling network that helps cells repair DNA damage caused by replication stress or external insults. DDR pathways, such as base-excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), non-homologous end-joining (NHEJ), and interstrand crosslink (ICL) repair, work together to maintain genomic stability. These pathways are closely linked to the innate and adaptive immune systems. For example, the cGAS–STING pathway detects DNA damage and activates immune responses, including the production of interferons (IFNs) and inflammatory cytokines. DDR components also directly influence immune responses by triggering programmed cell death or inflammatory signaling. Defective DDR can lead to genomic instability and immune dysfunction, contributing to diseases like cancer and autoimmune disorders. This review highlights the interaction between DDR and immune responses, emphasizing the role of DDR in modulating immune signaling pathways. DDR components, such as ATM, ATR, and DNA-PK, are crucial for DNA repair and also regulate immune responses. The cGAS–STING pathway is a key mediator of immune signaling in response to DNA damage. Additionally, DDR components like BRCA1, MRE11, and DNA-PK can directly sense DNA damage and activate immune responses. The innate immune system, including toll-like receptors (TLRs) and cytosolic DNA sensors, also interacts with DDR pathways. These interactions are essential for maintaining immune homeostasis and preventing diseases. The review also discusses the role of RNA sensors, such as RIG-I-like receptors, in detecting DNA damage and triggering immune responses. Overall, the interplay between DDR and immune responses is critical for maintaining genomic stability and preventing disease.DNA-damage response (DDR) is a complex signaling network that helps cells repair DNA damage caused by replication stress or external insults. DDR pathways, such as base-excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), non-homologous end-joining (NHEJ), and interstrand crosslink (ICL) repair, work together to maintain genomic stability. These pathways are closely linked to the innate and adaptive immune systems. For example, the cGAS–STING pathway detects DNA damage and activates immune responses, including the production of interferons (IFNs) and inflammatory cytokines. DDR components also directly influence immune responses by triggering programmed cell death or inflammatory signaling. Defective DDR can lead to genomic instability and immune dysfunction, contributing to diseases like cancer and autoimmune disorders. This review highlights the interaction between DDR and immune responses, emphasizing the role of DDR in modulating immune signaling pathways. DDR components, such as ATM, ATR, and DNA-PK, are crucial for DNA repair and also regulate immune responses. The cGAS–STING pathway is a key mediator of immune signaling in response to DNA damage. Additionally, DDR components like BRCA1, MRE11, and DNA-PK can directly sense DNA damage and activate immune responses. The innate immune system, including toll-like receptors (TLRs) and cytosolic DNA sensors, also interacts with DDR pathways. These interactions are essential for maintaining immune homeostasis and preventing diseases. The review also discusses the role of RNA sensors, such as RIG-I-like receptors, in detecting DNA damage and triggering immune responses. Overall, the interplay between DDR and immune responses is critical for maintaining genomic stability and preventing disease.