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After recognizing the major histocompatibility complex (MHC)\u2013peptide complex, cytokines including interferon-\u03b3 (IFN-\u03b3) are released to kill tumor cells. However, IFN-\u03b3 can also induce tumor cells to express PD-L1. This molecule can bind to PD-1 on the surface of T cells to exert inhibitory functions. In response to stimuli, like chemoradiotherapy or immunotherapy, tumor cells release damage-associated molecular patterns, including high-mobility group protein B1 (HMGB1). Our previous studies revealed that HMGB1 can increase the antitumor activity of T cells and enhance the secretion of cytokines, including IFN-\u03b3. However, the effect of HMGB1 on PD-L1 expression in non-small cell lung cancer remains unclear. Here, we examined the expression of HMGB1 and PD-L1 in tumor tissue slices of patients with non-small cell lung cancer with high expression of IFN-\u03b3 and observed that they exhibited a negative correlation, which was also verified by our analysis in The Cancer Genome Atlas. In vitro experiments demonstrated that HMGB1 could bind to RAGE (receptor for advanced glycation end products) and inhibit IFN-\u03b3 induction of PD-L1 by inhibiting the JAK1\/STAT3 pathway. In vitro and in vivo experiments indicated that HMGB1 enhanced the antitumor effects of chimeric antigen receptor T cells and inhibited tumor growth. These results showed that HMGB1 inhibited IFN-\u03b3\u2013induced PD-L1 expression, thereby enhancing the antitumor effects of T cells, and confirmed the role of HMGB1 as a prognostic indicator for lung cancer treated with chimeric antigen receptor T cells.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf125","type":"journal-article","created":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T16:19:57Z","timestamp":1751127597000},"page":"2480-2488","source":"Crossref","is-referenced-by-count":1,"title":["HMGB1 inhibits the IFN-\u03b3\u2013induced PD-L1 expression in NSCLC"],"prefix":"10.1093","volume":"214","author":[{"given":"Shumin","family":"Wang","sequence":"first","affiliation":[{"name":"Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan,","place":["P. R. 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China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7516-3047","authenticated-orcid":false,"given":"Wenhao","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University , Zhengzhou, Henan,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4023-2060","authenticated-orcid":false,"given":"Qitai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan,","place":["P. R. 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China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-7647","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9861-4681","authenticated-orcid":false,"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan,","place":["P. R. China"]},{"name":"School of Life Sciences, Zhengzhou University , Zhengzhou, Henan,","place":["P.R. China"]},{"name":"State Key Laboratory of Esophageal Cancer Prevention & Treatment , Zhengzhou, Henan,","place":["P.R. China"]},{"name":"Henan Key Laboratory for Tumor Immunology and Biotherapy , Zhengzhou, Henan,","place":["P.R. 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