Ataxia-Telangiectasia, DNA Repair Deficits, Immune Dysfunction, and Cancer: A Review of Mechanisms, Clinical Presentations, and Emerging Therapies.

Ataxia-Telangiectasia (A-T) is a rare, autosomal recessive disorder caused by biallelic pathogenic variants in the ATM gene. Loss of ataxia-telangiectasia mutated (ATM) protein function impairs DNA damage responses, leading to progressive neurodegeneration, genomic instability, immunodeficiency, and an increased risk of malignancy. Some A-T patients develop cancers at a young age and display extreme sensitivity to ionizing radiation and certain chemotherapeutics. Therefore, standard treatments often cause severe, life-threatening toxicities in these patients. This review discusses the dual role of ATM as a tumor suppressor and key DNA repair kinase, the mechanisms by which ATM deficiency promotes oncogenesis, and the unique challenges of treating malignancies in the context of A-T. We highlight emerging, less genotoxic therapies for ATM-deficient cancers including cancer vaccines, immune checkpoint inhibitors, CAR T-cell therapy, and synthetic lethal approaches such as Poly(ADP-ribose) polymerase (PARP) and Ataxia Telangiectasia and Rad3-related (ATR) inhibitors. These novel strategies may improve outcomes for A-T patients while minimizing treatment toxicity. We also outline future directions and clinical implications, emphasizing the need for tailored therapeutic approaches and multidisciplinary care for this high-risk population. Because prospective, A-T-specific therapeutic data are scarce, we draw extensively on the broader literature on somatic ATM-mutant cancers to inform management, while highlighting the additional constraints imposed by germline ATM loss.