Multinucleated giant cells in human pancreatic cancer are a distinct macrophage population undergoing a DNA damage response and associated to an aggressive tumor microenvironment [GeoMx DSP]

Spatial analyses revealed activation of hypoxia and extracellular matrix–remodeling pathways in MGC-associated niches, and experimental hypoxia promoted MGC formation in vitro. Consistently, a macrophage MGC gene signature was enriched in the squamous PDAC subtype and correlated with poorer overall survival in TCGA (p = 0.018). Morphometric and immunofluorescence analyses further showed increased 53BP1⁺/Ki67⁺ nuclei and nuclear atypia in MGCs, indicating ongoing proliferation despite DNA damage.

Together, these data identify multinucleated macrophages as a previously unrecognized immune cell state shaped by hypoxia and stress signaling, associated with aggressive tumor phenotypes, and potentially exploitable as an immune classifier in pancreatic cancer.