Traditionally considered as homogeneous innate immune cells, neutrophils are now found to exhibit phenotypic and functional heterogeneity. How to determine whether the functional changes of neutrophils are caused by activation or the result of gene reprogramming? Recent advances in multi-omics technologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, have comprehensively explained the mechanism of neutrophil heterogeneity. At the same time, artificial intelligence, especially machine learning, has promoted the in-depth analysis of multi-omics. Here, we introduce the latest progress in the discovery of neutrophil subsets by omics research. We will further discuss the application of machine learning in analyzing the heterogeneity of neutrophils through omics methods. Our goal is to provide a comprehensive overview of how machine learning and multi-omics are reshaping our understanding of neutrophil biology and pathophysiology.

Sepsis is a life‑threatening disease characterized by a dysregulated immune response, and neutrophils serve an important role in pathogen clearance, multiple organ failure and immune regulation. With the discovery of multiple phenotypical and functional variants of neutrophils in sepsis, the heterogeneity of neutrophils is crucial, as it impacts the effectiveness of the immune response and the overall outcome of sepsis. Various genome, transcriptome, proteome and metabolome properties may contribute to this heterogeneity. Multi‑omics approaches unveil complex details of neutrophil behavior in the context of sepsis, highlighting how neutrophil phenotypes are differentially recruited and activated in response to various stimuli. The present review aimed to provide an overview of the differences in neutrophil phenotypes and functions during sepsis, focusing on neutrophil heterogeneity identified via multi‑omics methods. Comprehensive understanding of multi‑omics data regarding neutrophil heterogeneity enhances the diagnostic accuracy of sepsis and provides a scientific basis for individualized treatment strategies, potentially improving patient outcomes by targeting specific neutrophil functions and states.