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Background Neutrophils within tumor microenvironment (TME) are increasingly recognized as key players in the cancer progression, exhibiting a dual role that fluctuate between pro-tumor and anti-tumor immune response.Methods Here, integrating in-house and public datasets RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (stRNA-seq) from cancer tissues was performed. In vitro and in vitro experiments was also performed.Results We identified a distinct HLA-DR +IGF1R+tumor associated neutrophils (TANs), which exhibit distinctive terminally differentiated and immunosuppressive characteristics. These cells predominantly localized to a hypoxic niche at the tumor core and favors tumor growth. This subset can prompt the transformation of CD4 T cells into regulatory T cells (Tregs), thereby augmenting the immunosuppressive profile of the PDAC microenvironment. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies. These neutrophils could further invoke both (neo)antigen-specific and antigen-independent T cell responses.Conclusions In essence, our study not only illuminated the distinctive transcriptomes of these tumor-specific neutrophils but also exposed the potential therapeutic advantages of targeting neutrophils in PDAC immunotherapy.