Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis

TL;DR

Chromosomal instability in esophageal cancer promotes tumor growth by triggering inflammation through a specific immune pathway.

Contribution

The study reveals a novel CIN-driven cGAS–chemokine–myeloid axis that promotes immunosuppression in esophageal adenocarcinoma.

Findings

CIN drives expression of myeloid-attracting chemokines like CXCL8 in EAC.

High CIN correlates with poor patient outcomes and disrupted cGAS–STING signaling.

CIN activates innate immune responses that lead to tumor-promoting inflammation.

Abstract

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, CINhigh, 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.

Chromosomal chaos rewires immune defense into tumor-promoting inflammation.

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