Abstract B080: Maturation-dependent sensing of microenvironmental cues drives divergent neutrophil polarity in pancreatic cancer

Abstract

Tumor-associated neutrophils exhibit functional heterogeneity, with distinct immunosuppressive and antigen-presenting states described across cancer types. Yet these populations have largely been characterized as isolated observations rather than as opposing fates arising from a common developmental decision point, and the mechanisms that specify each remain poorly understood. Here, using pancreatic ductal adenocarcinoma (PDAC) and its highly neutrophil-enriched tumor microenvironment (TME) as the disease context, we show that TGFβ-driven Siglec-F/8+ immunosuppressive and interferon-driven MHC-II+ antigen-presenting neutrophils represent opposing terminal fates governed by a binary transcriptional switch enforced by Zeb1 and Ets1. Competence to acquire each fate is gated by discrete windows of neutrophil maturation, which directs their segregation into spatially distinct niches within the PDAC TME and encodes divergent functional consequences for antitumor immunity. The resulting polarity is reflected in the circulating neutrophil compartment, where the balance between these states correlates with pathological response to neoadjuvant chemotherapy in patients with localized PDAC; pharmacological inhibition of the Siglec-F+ suppressive program improves chemosensitivity and survival in vivo, implicating neutrophil fate reprogramming as a novel immunomodulatory strategy in PDAC.