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Here, we demonstrate that (\n                    <jats:italic>\n                      Tmed4\n                      <jats:sup>\u0394Treg<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice with Treg-specific KO of ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) had more Tregs with impaired Foxp3 stability, Treg signatures, and suppressive activity, which led to T cell hyperactivation and an exacerbated inflammatory phenotype and boosted antitumor immunity in mice. Mechanistically, loss of\n                    <jats:italic>Tmed4<\/jats:italic>\n                    caused defects in ERS and a nuclear factor erythroid 2\u2013related factor 2\u2013related (NRF2-related) antioxidant response, which resulted in excessive ROS that reduced the Foxp3 stability and suppressive function of Tregs in an IRE1\u03b1\/XBP1 axis\u2013dependent manner. The abnormalities could be effectively rescued by the ROS scavenger, NRF2 inducer, or by forcible expression of IRE1\u03b1. Moreover, TMED4 suppressed IRE1\u03b1 proteosome degradation via the ER-associated degradation (ERAD) system including the ER chaperone binding immunoglobulin protein (BIP). Our study reveals that TMED4 maintained the stability of Tregs and their suppressive function through IRE1\u03b1-dependent ROS and the NRF2-related antioxidant response.\n                  <\/jats:p>","DOI":"10.1172\/jci179874","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T12:00:26Z","timestamp":1730376026000},"source":"Crossref","is-referenced-by-count":35,"title":["TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models"],"prefix":"10.1172","volume":"135","author":[{"given":"Zhenyan","family":"Jiang","sequence":"first","affiliation":[{"name":"Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital,"},{"name":"Hongqiao International Institute of Medicine, Shanghai Tongren Hospital,"},{"name":"Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, and"},{"name":"Shanghai Institute of Immunology, Department of Immunology 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