Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer

Authors

Schoenfeld, J., Noel, J., McGinnis, C., Fu, C., Alagesan, B., Hernandez, E., Jee, J., Schultz, N., Morris, Q., Lowe, S., Cloonan, S., Connolly, J., Chaligne, R., Kelsen, D., Yu, K., Zhang, W., OReilly, E., Satpathy, A., Ganz, T., Vardhana, S.

Abstract

Systemic iron sequestration occurs frequently in cancer due to inflammation-driven expression of the iron-regulatory hormone hepcidin. The impact of systemic iron availability on tumoral immunity is unclear. Here, we show that elevated serum hepcidin is associated with reduced survival and decreased intratumoral CD8+ T cells in patients with pancreas cancer. While hepcidin is not induced in murine tumor models, administration of a hepcidin mimetic phenocopies the T-cell-depleted tumor microenvironment seen in patients. Mechanistically, chronic antigen-driven mitochondrial dysfunction disrupts iron metabolism and selectively depletes high avidity CD8+ T cells during iron restriction. These findings establish a direct link between hepcidin-mediated iron sequestration and tumoral immunity and nominate systemic iron dysregulation as a therapeutic target to enhance anti-tumoral CD8+ T cell responses.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 26 Sep 2026.

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