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Ataxia telangiectasia mutated (<jats:italic>ATM<\/jats:italic>) is a central regulator of DNA double-strand break repair and is frequently affected by somatic or germline mutations in various cancer types, including breast, prostate, pancreatic, and lung cancer. However, the consequences of <jats:italic>ATM<\/jats:italic> loss on tumor immunogenicity are poorly understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We generated isogenic ATM-null models using CRISPR in murine triple-negative breast (4T1) and colorectal (CT26) cancer cell lines. ATM inactivation was confirmed by PCR and western blot. Immune cell infiltrates were assessed by flow cytometry and immunohistochemistry in both murine tumors and human samples from breast and lung cancers (via The Cancer Genome Atlas and institutional cohorts). In vivo, the impact of ATM loss on tumor growth and response to immune checkpoint blockade (anti-programmed cell death protein-1 (PD-1)) was evaluated. Furthermore, we compared the effects of different DNA-damaging agents\u2014including an ATR inhibitor (RP-3500), a PARP inhibitor (olaparib), and the topoisomerase II inhibitor etoposide\u2014on interferon-stimulated gene (ISG) expression and immune modulation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We find that\u2014in contrast to other DNA repair defects<jats:italic>\u2014ATM<\/jats:italic> deficiency (1) fails to encourage immune effector cell infiltration into tumors, and (2) does not enable immune cell recruitment via synthetic lethality strategies in clinical trials, such as with ATR inhibition. Assessing various DNA-damaging agents in <jats:italic>Atm<\/jats:italic> null tumors revealed a differential activation of type I interferon (IFN) signaling, with etoposide, a topoisomerase II inhibitor, emerging as the strongest activator of ISG under these conditions. Yet, PD-1-targeted immune checkpoint blockade does not bolster the therapeutic activity of etoposide in <jats:italic>Atm<\/jats:italic>-null syngeneic tumor models, nor does it modify the tumor microenvironment, suggesting that type I IFN signaling alone is insufficient to overcome immunosuppression in immunologically cold <jats:italic>ATM<\/jats:italic> null neoplasms.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ATM deficiency, while compromising DNA repair and enhancing sensitivity to radiation and ATR inhibition, does not increase tumor antigenicity or immunogenicity. Altogether, our results have important implications for the design of novel combination therapies for <jats:italic>ATM<\/jats:italic> null tumors and highlight the importance of antigenicity in the immunological consequences of defective DNA repair.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010548","type":"journal-article","created":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T07:45:16Z","timestamp":1746949516000},"page":"e010548","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["The cold immunological landscape of ATM-deficient cancers"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct04497116","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Sonali","family":"Sinha","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, 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