{
  "abstract": "Background Neutrophils are the first innate responders to intestinal dysbiosis, yet their stage-specific role in colorectal cancer (CRC) development remains poorly defined. While tumor-associated neutrophils (TANs) are implicated in advanced malignancy, their contribution to tumor initiation and their interaction with the early immune microenvironment are unclear. This study aims to identify the specific neutrophil subset and molecular orchestrators that translate microbial signals into a pro-tumorigenic inflammatory niche during early CRC.Methods We employed time-dependent neutrophil depletion (anti-Ly6G) and neutrophil-specific genetic models (ncf1 fl/fl and Fnip1 fl/fl) in AOM/DSS-induced mouse model. We integrated single-cell RNA sequencing (scRNA-seq) and high-plex spatial proteomics (24-antibody panel) to dissect the neutrophil-microbiota-Treg interactome. Bacterial recruitment and activation were validated using pathogenic (B. fragilis), non-pathogenic (E. coli), and probiotic (L. johnsonii) strains.Results Early neutrophil infiltration is a prerequisite for CRC progression via establishing a pro-tumorigenic microenvironment through p47phox-dependent reactive oxygen species (ROS) release. Single-cell RNA sequencing and high-plex spatial proteomics revealed that these neutrophils, specifically a Fnip1+ subcluster, create a localized ‘oxidative barrier’ that spatially excludes and functionally disarms regulatory T cells (Tregs). This spatial segregation prevents the resolution of early inflammation, fostering an environment conducive to tumor growth. Mechanistically, we found that pathogenic microbiota (B. fragilis and S. gallolyticus) recruit and activate these neutrophils via the TLR-MyD88-AMPK signaling axis. This pathway orchestrates Fnip1-TFEB-mediated lysosomal biogenesis, providing a functional platform necessary for massive ROS production and prolonged neutrophil survival within the tumor niche. Notably, while certain probiotics (L. johnsonii) can trigger ROS via direct contact, only cell-invasive pathogens possess the capacity for persistent recruitment and tumor promotion.Conclusions Our findings define Fnip1+neutrophils as the primary architects of the early pro-tumorigenic niche. By linking microbial invasion to a neutrophil-driven oxidative barrier, we provide a novel mechanistic framework for CRC initiation. These results position the Fnip1-lysosome-ROS axis as a valuable therapeutic target for the early interception of microbiota-driven colorectal cancer.",
  "authors": [
    {
      "affiliations": [
        "Institute of Chinese Medical Sciences, University of Macau, Macau"
      ],
      "name": "Chuangen Li"
    }
  ],
  "title": "IDDF2026-ABS-0298 Fnip1+neutrophils translate microbial signaling into pro-tumorigenic responses during early colonic tumorigenesis",
  "uid": "3377d123-25e8-50f3-af1a-036c6cd413ba"
}