Pan-cancer single-cell dissection identifies conserved pro-tumorigenic VEGFA+ and CD274+ neutrophils

Abstract Tumor-associated neutrophils (TANs) are critical components in cancer progression, yet the conserved programs in pan-cancer that shape tumor evolution remain incompletely defined. Here, we integrated single-cell RNA sequencing (scRNA-seq) data from 545,538 neutrophils from 486 donors across 16 cancer types, inflammatory conditions, and healthy tissues. We identified VEGFA + and CD274 + neutrophil subsets that are consistently present across multiple cancer types and exhibit distinct spatial niches: VEGFA + neutrophils colocalized with endothelial cells, whereas CD274 + neutrophils were proximal to exhausted T cells. Mechanistically, VEGFA + neutrophils potentiated angiogenesis through VEGFA-VEGFR interactions with endothelial cells, while CD274 + neutrophils suppressed T cells through the CD274-PDCD1 axis. Clinically, a high abundance of VEGFA + neutrophils was associated with poor survival across multiple cancers, whereas greater baseline levels of CD274 + neutrophils were associated with improved immunotherapeutic responses. Both neutrophil subsets exhibited terminal differentiation states governed by distinct transcription factor (TF) regulatory networks. Collectively, these findings delineate conserved, pro-tumorigenic neutrophil programs across diverse cancer types, nominating actionable targets and predictive biomarkers for cancer therapy.