Tumor Cell–Intrinsic <i>Decr2</i> Regulates Ferroptosis and Immunotherapy Efficacy

Immune checkpoint blockade therapies have transformed the landscape of cancer care, but durable clinical responses are achieved in only a subset of patients. To identify genes that can contribute to immunotherapy resistance, a genome-wide CRISPR screen was performed. Selection for mutants that are resistant to T cell-mediated killing identified the gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase. We show that Decr2 in tumor cells participates in CD8+ T cell-mediated tumor cell killing and that Decr2 knockdown reduces the efficacy of anti-PD-L1 therapy in vivo. Knocking down Decr2 expression resulted in diminished ferroptosis that was associated with reduced induction of polyunsaturated ether phospholipids. Analysis of tumor RNA sequencing data from patients with melanoma revealed that upregulation of Decr2 was associated with anti-PD-1 efficacy, and patients with Decr2 gene deletions showed worse clinical outcomes. Our results identify Decr2 as a regulator of immunomediated tumor cell killing, with implications for improving immunotherapy efficacy.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-06-13
DOI
https://doi.org/10.1158/2326-6066.cir-24-0519
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
0.00

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Tumor Cell–Intrinsic Decr2 Regulates Ferroptosis and Immunotherapy Efficacy

Justin Paul Kline, Jonathan Trujillo, Yuanyuan Zha, Ruxandra Tonea et al.
Cancer Immunology Research
Ferroptosis and cancer prognosis
article

Tumor Cell–Intrinsic Decr2 Regulates Ferroptosis and Immunotherapy Efficacy

Justin Paul Kline, Jonathan Trujillo, Yuanyuan Zha, Ruxandra Tonea, Alexandra Cabanov, Lishi Xie, Yaopeng Li, Hardik Shah, Shuyin Li, Blake Flood, Jason W. Shapiro, Emily F. Higgs, Tyler A. Jones, Thomas F. Gajewski, Ken Hatogai
article en

Abstract

Immune checkpoint blockade therapies have transformed the landscape of cancer care, but durable clinical responses are achieved in only a subset of patients. To identify genes that can contribute to immunotherapy resistance, a genome-wide CRISPR screen was performed. Selection for mutants that are resistant to T cell-mediated killing identified the gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase. We show that Decr2 in tumor cells participates in CD8+ T cell-mediated tumor cell killing and that Decr2 knockdown reduces the efficacy of anti-PD-L1 therapy in vivo. Knocking down Decr2 expression resulted in diminished ferroptosis that was associated with reduced induction of polyunsaturated ether phospholipids. Analysis of tumor RNA sequencing data from patients with melanoma revealed that upregulation of Decr2 was associated with anti-PD-1 efficacy, and patients with Decr2 gene deletions showed worse clinical outcomes. Our results identify Decr2 as a regulator of immunomediated tumor cell killing, with implications for improving immunotherapy efficacy.

Cancer Immunology ResearchVol. 13(8)
University of Illinois Chicago (US), University of Chicago (US), May Institute (US), University of Chicago Medicine Comprehensive Cancer Center
Bristol-Myers Squibb, University of Chicago, National Cancer Center, University of Chicago Medicine, Comprehensive Cancer Center, University of Chicago Medical Center
Openalex Percentile: Top 78%
Ferroptosis and cancer prognosis
DOIOpen Access PDFOpenAlex
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