Bruno Beernaert, Rose L. Jady-Clark, Parin Shah, Erik Ramon-Gil, Nora Lawson, Zack D Brodtman, Somnath Tagore, Frederik Stihler, A. Carter, Shannique Clarke, Tong Liu, Winston M. Zhu, Juliet E. Martin, Erkin Erdal, Alistair Easton, Leticia Campo, Molly Browne, Stephen Ash, Rabial Q. Raja, Nicola Waddell, Tom Crosby, Simon Lord, DA Mann, Ignacio Melero, Carlos E. de Andrea, Andréa E. Tijhuis, Floris Foijer, Ester M. Hammond, Kadir C. Akdemir, Jack Leslie, Benjamin Izar, Eileen E. Parkes
Chromosomal instability (CIN), a pervasive feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and metastasis. CIN stimulates the cGAS–STING pathway, typically linked to antitumor immunity. However, despite the high CIN burden in EAC, the cGAS–STING pathway remains largely intact. To address this paradox, we interrogated multiple esophageal cancer models, finding myeloid-attracting chemokines—with CXCL8 as a prominent hit—as conserved CIN-driven targets in EAC. Using multiplexed immunofluorescence microscopy, we quantified ongoing CIN in human EAC tumors by measuring cGAS-positive micronuclei, validated by whole-genome sequencing. Coupling in situ CIN detection with single-nucleus RNA sequencing and multiplex immunophenotyping of human EAC, we link CIN to tumor-intrinsic innate immune activation, CXCL8 expression, and myeloid cell–mediated immunosuppression. In patients with EAC, CIN high , myeloid-dominated tumors correlate with poor outcomes and aberrant cGAS–STING signaling. These insights explain the counterintuitive maintenance of cGAS–STING and highlight the disruption of the CIN–cGAS–inflammation axis as a potential therapeutic strategy in EAC.