Abstract A034: Cancer neutrophil encyclopedia: A deep dive into antigen-presenting warriors

Abstract Neutrophils, the most efficient defenders against pathogens, are essential for tumor microenvironment balance and homeostasis. However, given their plasticity and short half-life which made them too fragile to be profiled, it poses complex challenges regarding how neutrophils are imprinted and adapt specific fates across cancers. Here we designed a one-two-punch sorting strategy, generated the neutrophil atlas from 225 samples of 144 patients from 17 cancer types, and further developed a computational pipeline to recover both shared and specific transcriptional programs. Unexpectedly, neutrophils harbored extraordinary complexity composed of 10 cell states and showed sharp tissue or phenotypic specialty. We observed and verified that cancer neutrophils are dramatically arranged along tumor-specific terminal differentiation paths such as inflammation, angiogenesis and antigen-presenting. In particular, the antigen-presenting program was associated with better patient outcomes in the majority of cancers. Such a program can be evoked by leucine metabolism and is dependent on mitochondrial remodeling, acetyl-CoA generation, and preferable epigenetic histone H3K27ac modification. Functionally, antigen-presenting neutrophils invoked expanded T cell response and neoantigen-specific reactiveness. We finally designed the antigen-presenting neutrophil immunotherapy (adoptive transferring and leucine diet) which fine-tunes the microenvironment balance and fuels anti-PD-1 immunotherapy. In summary, these data not only lay the groundwork for future neutrophil research, and open the black box of neutrophil state divergence across cancers, but also unravel minimally invasive therapeutic opportunities including adoptive transferring antigen-presenting neutrophils. Citation Format: Yingcheng Wu. Cancer neutrophil encyclopedia: A deep dive into antigen-presenting warriors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A034.