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Existing prognostic systems, such as IPSS\u2010R and IPSS\u2010M, do not incorporate immune alterations. We assessed the biological and clinical relevance of an immune dysfunction signature (IDS) across multi\u2010center MDS and CMML cohorts. IDS scores, derived from bulk transcriptomic data, were significantly associated with inferior leukemia\u2010free and overall survival. In multivariable analyses, IDS retained independent prognostic value alongside IPSS\u2010R, IPSS\u2010M, and bi\u2010allelic TP53 inactivation. Incorporation of IDS into existing models improved prognostic discrimination and time\u2010dependent predictive accuracy. Longitudinal analyses revealed that rising IDS scores paralleled disease progression and acute transformation, whereas declining scores were observed in remission. Biologically, IDS\u2010high cases demonstrated reduced cytotoxic T\u2010cell activity, expansion of regulatory T cells, enrichment of primitive progenitor signals, and increased expression of checkpoint pathway genes. These findings were validated across multiple independent MDS cohorts and consistently reproduced in CMML, where IDS also stratified risk and tracked disease evolution. Finally, integration with drug response signatures from the BeatAMLv2 cohort suggested potential therapeutic vulnerability of IDS\u2010high cases to multikinase and NF\u2010\u03baB pathway inhibitors. These results establish IDS as a robust and dynamic biomarker in MDS and CMML, with applications in refined risk stratification, longitudinal disease monitoring, and guiding personalized therapeutic strategies targeting immune dysfunction.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    #201709072RINC, #202109078RINB, #202207050RINB\n                  <\/jats:p>","DOI":"10.1111\/cas.70405","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T07:02:11Z","timestamp":1777359731000},"page":"1921-1934","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An Immune Dysfunction Signature Score Predicts Survival in\n                    <scp>MDS<\/scp>\n                    Patients: Insights From a Longitudinal, Multicenter 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