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Mutational instability involves excessive accumulation of small-scale alterations, such as substitutions and indels, from defective DNA repair or aberrant mutagenic processes, generating neoantigens and increased immunogenicity. Chromosomal instability encompasses large-scale alterations in which cells gain, lose, or rearrange chromosomes, resulting in aneuploidy and immune evasion through chronic innate activation and myeloid remodeling. This review outlines differences between mutational and chromosomal instability and discuss how their interplay shapes tumor immunogenicity and response to immunotherapy. Understanding these opposing mechanisms could inform immunotherapeutic approaches in cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Mutational and chromosomal alterations exert opposing effects on antitumor immunity. Hypermutated tumors can generate abundant neoantigens that prime adaptive immunity and sensitize tumors to checkpoint blockade. In contrast, chromosomal instability triggers chronic innate immune signaling that is paradoxically immunosuppressive, in part through myeloid cell and T-cell dysfunction. Integrating both processes into a unified framework could help uncover mechanisms of immune evasion and guide personalized immunotherapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-2063","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:11:53Z","timestamp":1790838713000},"page":"1973-1991","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunologic Consequences of Genomic Instabilities"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2303-118X","authenticated-orcid":false,"given":"Emily","family":"Alouani","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Memorial Sloan Kettering Cancer Center 1 , New York, New York."},{"id":[{"id":"https:\/\/ror.org\/0321g0743","id-type":"ROR","asserted-by":"publisher"}],"name":"Gustave Roussy 2 , Villejuif, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-941X","authenticated-orcid":false,"given":"Jean-David","family":"Fumet","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0321g0743","id-type":"ROR","asserted-by":"publisher"}],"name":"Gustave Roussy 2 , Villejuif, France."},{"name":"3Centre Georges-Fran\u00e7ois Leclerc, Unicancer, Cancer Biology Transfer Platform, UMR INSERM 1231, TIRECs Team, Universit\u00e9 Bourgogne Europe, Dijon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9264-8327","authenticated-orcid":false,"given":"Paul","family":"Johannet","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Memorial Sloan Kettering Cancer Center 1 , New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-3019","authenticated-orcid":false,"given":"Aur\u00e9lien","family":"Marabelle","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0321g0743","id-type":"ROR","asserted-by":"publisher"}],"name":"Gustave Roussy 2 , Villejuif, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1594-4827","authenticated-orcid":false,"given":"Benoit","family":"Rousseau","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Memorial Sloan Kettering Cancer Center 1 , New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2026100103114727400_bib1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1126\/science.aaa1348","article-title":"Cancer immunology. 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