Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer
- 1Memorial Sloan Kettering Cancer Center
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.
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BibTeX
@misc{schoenfeld2026systemic,
title = {{Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer}},
author = {J. Schoenfeld and J. Noel and C. McGinnis and C. Fu and B. Alagesan and E. Hernandez and J. Jee and N. Schultz and Q. Morris and S. Lowe and S. Cloonan and J. Connolly and R. Chaligne and D. Kelsen and K. Yu and W. Zhang and E. OReilly and A. Satpathy and T. Ganz and S. Vardhana},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753167},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753167v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer
AU - J. Schoenfeld
AU - J. Noel
AU - C. McGinnis
AU - C. Fu
AU - B. Alagesan
AU - E. Hernandez
AU - J. Jee
AU - N. Schultz
AU - Q. Morris
AU - S. Lowe
AU - S. Cloonan
AU - J. Connolly
AU - R. Chaligne
AU - D. Kelsen
AU - K. Yu
AU - W. Zhang
AU - E. OReilly
AU - A. Satpathy
AU - T. Ganz
AU - S. Vardhana
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753167
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753167v1
AB - 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.
ER -