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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\u2010tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF\u2010\u03b1, CXCL9, and CXCL10. However, using a cystine\u2010free diet marginally reduces the development of lung cancer in vivo. A cystine\u2010free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin\u2010mediated transport inhibition increased PD\u2010L1 expression in macrophages both in vitro and in vivo. Combining a cystine\u2010free diet or IKE injection with PD\u2010L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency\u2010induced GSH depletion activates NF\u2010\u03baB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF\u2010\u03baB 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\u2010L1 inhibition is a promising therapeutic strategy.<\/jats:p>","DOI":"10.1002\/advs.202413084","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T10:53:13Z","timestamp":1752144793000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0762-5946","authenticated-orcid":false,"given":"Yun","family":"Xu","sequence":"first","affiliation":[{"name":"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"},{"name":"Zhejiang Key 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