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journal article·2025-09Open access

Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition

Yun Xu, Shumin Li, Jiaji Wu, Shumin Xu, Mo Shen, Chenyang Wang, Andreas Lundqvist, Jianghao Yu, Zhiyong Xu, Yueli Shi, Nana Liu, Yunke Yang, Jiangnan Zhao, Ying Yang, Pingli Wang, Peng Yi, Jin Cheng, Junhui Sun, Mengshu Li, Peng Xiao, Kai Wang

Advanced Science· Volume 12· Issue 35
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Abstract

Abstract Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has shown promising therapeutic effects in the treatment of lung cancer, the overall efficacy of PD‐1/PD‐L1 inhibitors is only 20%‐30%. Thus, more effective combination therapies are needed. This study finds that cystine and cysteine levels in tumor tissues of lung cancer patients are significantly higher than adjacent non‐tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF‐α, CXCL9, and CXCL10. However, using a cystine‐free diet marginally reduces the development of lung cancer in vivo. A cystine‐free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin‐mediated transport inhibition increased PD‐L1 expression in macrophages both in vitro and in vivo. Combining a cystine‐free diet or IKE injection with PD‐L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency‐induced GSH depletion activates NF‐κB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF‐κB inhibitor. At the same time, lung cancer patients with better responses to immunotherapy are found to have lower serum GSH levels. These findings suggest that targeting cystine metabolism combined with PD‐L1 inhibition is a promising therapeutic strategy.
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Research context

OpenAlex topics: Immune cells in cancer · Amino Acid Enzymes and Metabolism · Epigenetics and DNA Methylation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Respiratory and Critical Care Medicine Center for Oncology Medicine the Fourth Affiliated Hospital of School of Medicine International School of Medicine International Institutes of Medicine Zhejiang University Yiwu 322000 China

Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer Yiwu 322000 China

Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325015 China

Shanghai Fengxian District Central Hospital Shanghai 201400 China

Department of oncology Beijing Chest Hospital Capital Medical University Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing 101149 China

Department of Oncology‐Pathology Karolinska Institutet Stockholm 17177 Sweden

Department of cardiothoracic surgery Center for Oncology Medical the Fourth Affiliated Hospital of School of Medicine International School of Medicine International Institutes of Medicine Zhejiang University Yiwu 322000 China

Department of Respiratory and Critical Care Medicine The Second Affiliated Hospital of Zhejiang University School of Medicine No. 1511, Jianghong Road Hangzhou 310003 China

The Quzhou Affiliated Hospital of Wenzhou Medical University Quzhou People's Hospital Quzhou 324000 China

The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University Wuxi Center for Disease Control and Prevention Wuxi 214023 China

Department of Reproductive Medicine Center The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325015 China

Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou 310015 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China

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