A new study identifies multinucleated giant macrophages as a hallmark of aggressive pancreatic cancer

A new study published in Cancer Immunology Research, one of the official journals of the American Association for Cancer Research (AACR), identifies a previously unrecognized population of macrophages in human pancreatic cancer and provides new insights into how the tumor microenvironment shapes immune cell behavior.

The study, led by Dr. Federica Marchesi, founder of the Italian Pancreatic Cancer Community (iPCC), investigated a previously unrecognized subset of tumor-associated macrophages in pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive and treatment-resistant human malignancies.

Viatore and colleagues identified a distinct population of multinucleated giant cells (MGCs) of macrophage origin, characterized by multiple and irregular nuclei. These cells were detected in approximately one third of pancreatic cancer specimens and were particularly enriched in tumors displaying aggressive squamous features.

Using spatial transcriptomics, advanced imaging technologies and functional experimental models, the authors demonstrated that the giant macrophages are characterized by activation of hypoxia-related pathways, MYC signaling, oxidative stress responses, and DNA damage response programs. Importantly, hypoxic conditions were sufficient to promote the formation of multinucleated macrophages in vitro, suggesting that the harsh tumor microenvironment directly contributes to their development.

The study also showed that a gene signature associated with these cells correlates with the squamous molecular subtype of pancreatic cancer and predicts poorer patient survival. Furthermore, multinucleated macrophages were more frequently observed in tumors exposed to neoadjuvant chemotherapy, suggesting that tissue stress and treatment-induced damage may contribute to their emergence.

These findings identify multinucleated giant macrophages as a previously unrecognized immune cells in pancreatic cancer and suggest that they may represent novel biomarkers of aggressive disease biology.
The work was performed by researchers from the University of Milan and Humanitas Research Hospital, in collaboration with several national partners, including Vincenzo Corbo from the University of Verona.

As efforts continue to develop more effective immunotherapeutic strategies for pancreatic cancer, a deeper understanding of the immune ecosystem surrounding tumor cells remains essential. This study adds an important new piece to that puzzle and further highlights the complexity of macrophage biology in pancreatic cancer.

Reference

Viatore M, Polidori R, Putignano AR, et al. Multinucleated giant cells in human pancreatic cancer are a distinct macrophage population undergoing a DNA damage response and associated with an aggressive tumor microenvironment. Cancer Immunology Research. 2026.