Cooperative response loops enhanced by histamine signaling during tumor-neutrophil crosstalk in pleural mesothelioma

Cell Reports 2026 May 26 [Link]

Kuniyo Sueyoshi, Miwako Kakiuchi, Daisuke Komura, Hiroto Katoh, Asami Yamamoto, Susumu Kirimura, Iichiroh Onishi, Ayaka Asakawa, Hironori Ishibashi, Kenichi Ohashi, Kenichi Okubo, Shumpei Ishikawa

Abstract

Pleural mesothelioma (PM) is an aggressive malignancy marked by substantial intratumor heterogeneity. A subset enriched in neutrophils correlates with poor prognosis, yet the underlying mechanisms and targetable pathways remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) of neutrophilic PM and established matched patient-derived xenograft (PDX) models that recapitulate intratumor subpopulations with varying neutrophil infiltration. This approach enabled controlled, clinically relevant setups for analyzing neutrophil-tumor dynamics. Infiltrating neutrophils adopted a regenerative, tumor-promoting phenotype. Notably, we identified neutrophil-derived histamine as a key mediator of tumor motility and inflammatory signaling, forming a targetable feedback loop through reciprocal interactions. We further uncovered that BAP1 mutation status was linked with clinical neutrophil enrichment; CRISPR-Cas9-mediated BAP1 knockout reduced chemotactic gene expression and chromatin accessibility at regulatory regions. By revealing how tumors reprogram neutrophils, this study lays the groundwork for histamine-targeted interventions and rational patient stratification, aiming for more precise control of PM.