ENDOD1 (endonuclease domain containing 1) is a transmembrane nuclease with dual roles in DNA repair and innate immunity. As a DNase and RNase, ENDOD1 generates 5' overhangs through its endonuclease and 3'→5' exonuclease activities, facilitating non-homologous end joining (NHEJ)-dependent repair of double-stranded DNA breaks at the nuclear periphery 1. The protein functions downstream of DNA-dependent protein kinase catalytic subunit and promotes repair of heterochromatic and telomeric DNA lesions 1. In innate immunity, ENDOD1 modulates cGAS-STING signaling through interaction with RNF26. Clinically, ENDOD1 acts as a tumor suppressor. Loss of ENDOD1 is synthetic lethal with homologous recombination defects and TP53 mutations, causing DNA damage accumulation and cell death 2. In prostate cancer, ENDOD1 is downregulated in high-grade and metastatic disease, with overexpression suppressing proliferation and invasion 3. Its therapeutic potential is substantial: mouse EndoD1 knockdown is well-tolerated, and human ENDOD1 targeting restrains TP53-mutated tumor progression in xenografts 2. Since ~50% of tumors harbor TP53 mutations, ENDOD1 represents a wide-spectrum synthetic lethal target for cancer therapy 2.