Immunotherapy has revolutionized cancer treatment, particularly with immune checkpoint inhibitors (ICIs), which harness the immune system to achieve durable antitumor responses. DNA repair pathways, essential for maintaining genomic stability, play a complex role in cancer. While functional DNA repair prevents tumorigenesis, deficiencies in pathways such as homologous recombination (HR), mismatch repair (MMR), and non-homologous end joining (NHEJ) can amplify tumor immunogenicity. These deficiencies increase tumor mutational burden, generate neoantigens, and activate innate immune sensors like cGAS–STING and RIG-I/MDA5-MAVS. Therapies such as radiotherapy and chemotherapy can enhance these effects by inducing DNA damage and de-repressing endogenous retroviral elements, creating a "viral mimicry" state that promotes immune recognition. Thus, combining DNA repair inhibitors with cytotoxic therapies and immunotherapy has emerged as a promising strategy to enhance antitumor immunity. This review highlights mechanisms by which DNA repair defects and genotoxic stress activate innate immunity, improve antigen presentation, and foster T-cell activation. Emerging approaches integrating PARP and ATM/ATR inhibitors with ICIs, STING agonists, and cancer vaccines offer potential to overcome immune resistance. Personalized combinations tailored to tumor-specific DNA repair and immune profiles hold promises for transforming cancer treatment, with ongoing research aimed at optimizing therapeutic efficacy while minimizing toxicity.