Systemic iron sequestration restricts the intratumoral CD8 + T cell landscape in pancreas cancer
Year: 2026
Type: preprint
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.
Authors: Joshua D. Schoenfeld, Jahi J. Noel, Christopher S. McGinnis, Chenlian Fu, Brinda Alagesan, Eduardo Hernandez, Justin Jee, Nikolaus Schultz, Quaid Morris, Scott Lowe, Suzanne M. Cloonan, John E. Connolly, Ronan Chaligne, David Kelsen, Kenneth H. Yu, William Z. Zhang, Eileen M. O’Reilly, Ansuman T. Satpathy, Tomas Ganz, Santosha A. Vardhana
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1558408032, G1978554689, G2051006376, G2171762837, G289723095, G3305280596, G4102770861, G4425862374, G5627732322, G7699268406, G8091674619, G8904650876, G9000003249, G9000192777, Cancer Center Support Grant, MSK Paul Calabresi Career Development Award for Clinical Oncology, Investigational Cancer Therapeutics Training Program (ICTTP), The Memorial Sloan Kettering Cancer Center SPORE in Pancreas Cancer, G957729743
OpenAlex ID: W7214503420