DNA repair at the crossroads of tumor immunogenicity and cancer therapy: Harnessing innate and adaptive immune pathways for improved therapeutic outcomes

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.