Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis.

Authors

Douglas E Biancur, Harsha Venkatesh, Amy Crawford, Yealeen Jeong, Albert S W Sohn, Kevin S Kapner, Keisuke Yamamoto, Elaine Y Lin, Robert S Banh, Mohamad Assi, Beny Shapiro, Peter Yu, Soomin C Song, William A Coetzee, Andrew J Aguirre, Alisha N Jones, Alec C Kimmelman, Richard Possemato

Published in

Science advances. Volume 12. Issue 29. Pages eadz8681. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.

PMID:
42467776
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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