PCSK9 drives acquired resistance to anti-PD-1 immunotherapy through cystine metabolic reprogramming in lung cancer
4 affiliations
- 1Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 2Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- 3Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 4Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Abstract
Background: Acquired resistance (AR) represents a major obstacle to immune checkpoint inhibitor (ICI) therapy in lung cancer. However, its underlying mechanisms and reversal strategies remain unclear.
Methods: In this study, we analyzed paired tumor specimens from patients with AR to anti-programmed cell death protein 1 (PD-1) therapy and used mouse AR models, together with transcriptomic and metabolomic analyses, to investigate resistance mechanisms in lung cancer.
Results: We identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as a key mediator of AR to anti-PD-1 therapy that suppresses CD8+ T-cell function by reprogramming cystine metabolism in the tumor microenvironment. Mechanistically, PCSK9 interacts with KEAP1 (kelch-like ECH-associated protein 1) and facilitates its lysosomal degradation, leading to upregulation of the cystine transporter SLC7A11 in tumor cells. Elevated SLC7A11 enhances cystine uptake by tumor cells, limiting its availability for CD8+ T cells and impairing their effector function. Furthermore, we demonstrate that PCSK9 upregulation in resistant tumors is induced by interferon-γ via the JAK1/2–STAT1 signaling axis. Importantly, inhibition of PCSK9 alleviates tumor-driven cystine competition, restores CD8+ T-cell function, and resensitizes resistant tumors to anti-PD-1 therapy.
Conclusions: These findings uncover a tumor-intrinsic immunometabolic mechanism of AR, wherein PCSK9 drives cystine competition between tumor cells and CD8+ T cells and highlight PCSK9 as a potential metabolic checkpoint for overcoming AR in immune checkpoint inhibitor therapy.
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BibTeX
@article{jie2026pcsk9,
title = {{PCSK9 drives acquired resistance to anti-PD-1 immunotherapy through cystine metabolic reprogramming in lung cancer}},
author = {Guangling Jie and Zhengqi Cao and Jingze Wang and Wenqing Lu and Xiaokuan Zhu and Ziming Li and Ying Wang and Shun Lu and Liliang Xia},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-015974},
url = {https://doi.org/10.1136/jitc-2026-015974},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - PCSK9 drives acquired resistance to anti-PD-1 immunotherapy through cystine metabolic reprogramming in lung cancer
AU - Guangling Jie
AU - Zhengqi Cao
AU - Jingze Wang
AU - Wenqing Lu
AU - Xiaokuan Zhu
AU - Ziming Li
AU - Ying Wang
AU - Shun Lu
AU - Liliang Xia
PY - 2026
DA - 2026/10/20
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-015974
UR - https://doi.org/10.1136/jitc-2026-015974
AB - Background: Acquired resistance (AR) represents a major obstacle to immune checkpoint inhibitor (ICI) therapy in lung cancer. However, its underlying mechanisms and reversal strategies remain unclear. Methods: In this study, we analyzed paired tumor specimens from patients with AR to anti-programmed cell death protein 1 (PD-1) therapy and used mouse AR models, together with transcriptomic and metabolomic analyses, to investigate resistance mechanisms in lung cancer. Results: We identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as a key mediator of AR to anti-PD-1 therapy that suppresses CD8+ T-cell function by reprogramming cystine metabolism in the tumor microenvironment. Mechanistically, PCSK9 interacts with KEAP1 (kelch-like ECH-associated protein 1) and facilitates its lysosomal degradation, leading to upregulation of the cystine transporter SLC7A11 in tumor cells. Elevated SLC7A11 enhances cystine uptake by tumor cells, limiting its availability for CD8+ T cells and impairing their effector function. Furthermore, we demonstrate that PCSK9 upregulation in resistant tumors is induced by interferon-γ via the JAK1/2–STAT1 signaling axis. Importantly, inhibition of PCSK9 alleviates tumor-driven cystine competition, restores CD8+ T-cell function, and resensitizes resistant tumors to anti-PD-1 therapy. Conclusions: These findings uncover a tumor-intrinsic immunometabolic mechanism of AR, wherein PCSK9 drives cystine competition between tumor cells and CD8+ T cells and highlight PCSK9 as a potential metabolic checkpoint for overcoming AR in immune checkpoint inhibitor therapy.
SN - 2051-1426
ER -