NFE2-driven neutrophil polarization promotes pancreatic cancer liver metastasis progression

Pancreatic cancer liver metastasis (PCLM) is an important factor leading to dismal prognosis. The adaptive remodeling of the tumor microenvironment (TME), especially the role of neutrophil in liver metastasis remains elusive. Here we combined single-cell sequencing combined with spatial transcriptomics on patients’ samples to characterize the landscape of PCLM, and explored the functional diversity possessed by neutrophils infiltrated in liver metastases. We identified the pivotal Neutrophils_S100A12 cluster capable of promoting metastatic progression by releasing neutrophil extracellular traps (NETs); spatially, Neutrophils_S100A12 cells are specifically distributed at the invasive front of the metastatic lesions. Mechanistically metastatic TME activates canonical TGF-β/SMAD3 signaling within neutrophil, resulting in NFE2-mediated phenotypic polarization; furthermore NFE2 induces NETs generation by up-regulating PADI4 expression. Interference with NFE2 activation in neutrophils prevents phenotypic conversion and reduces liver metastasis. Our data demonstrate that NFE2-mediated neutrophil polarization in PCLM is a potential target for anti-metastatic therapy.