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Here, we introduce APEX (Associating Plasma Epigenomic features with eXpression), a framework for inferring expression from circulating cell-free chromatin. Trained on \u223c270,000 gene\u2013sample pairs from matched tumor RNA-seq and plasma cfChIP-seq across multiple cancers and validated on &gt;15 unseen cancer subtypes, APEX accurately infers cancer gene expression across a range of tumor fractions and outperforms existing plasma-based approaches by integrating positional histone mark and DNA fragmentation patterns across promoters and gene bodies. Using plasma alone, APEX enables classification of prognostically relevant basal and classical pancreatic cancer subtypes and identifies plasma-inferred\n                  <jats:italic>NECTIN4<\/jats:italic>\n                  expression as a biomarker of response to enfortumab vedotin in metastatic bladder cancer. Together, these findings establish APEX as a biopsy-free approach for profiling tumor transcriptional states and extend liquid biopsy beyond genomic alterations to clinically relevant gene expression programs.\n                <\/jats:p>","DOI":"10.64898\/2026.02.18.706026","type":"posted-content","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T01:15:21Z","timestamp":1771550121000},"source":"Crossref","is-referenced-by-count":4,"title":["Integrated inference of cancer gene expression from cell-free plasma chromatin"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2798-6220","authenticated-orcid":false,"given":"Gunsagar S.","family":"Gulati","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, 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