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

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.