{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:52Z","timestamp":1789448572438,"version":"build-2803163510"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011789","name":"Department of Science and Technology of Jilin Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011789","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cancer stem cells (CSCs) are critical drivers of tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, how CSCs remodel the immunosuppressive tumor microenvironment (TME) of NSCLC remains largely unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Flow cytometry was performed to evaluate the immunomodulatory effects of NSCLC CSCs on T cell differentiation. RNA-sequencing-based metabolic profiling was conducted to identify pivotal metabolic pathways activated in CSCs. Mitochondrial reactive oxygen species (ROS) encapsulated in CSC-derived exosomes were quantified, and the molecular mechanism by which exosomal ROS modulates intracellular nitric oxide (NO) production and FoxP3 post-translational modifications in T cells was further explored. Patient-derived organoids (PDOs) were utilized as a preclinical model to verify the therapeutic potential of glutamine metabolism targeting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NSCLC CSCs potently induced tumor immunosuppression by promoting regulatory T (Treg) cell differentiation. Mechanistically, hyperactive glutamine metabolism in CSCs substantially increased mitochondrial ROS generation. Exosomal ROS secreted by CSCs was transferred to T cells, thereby elevating intracellular NO synthesis. Increased NO further triggered S-nitrosylation and deubiquitination of FoxP3, which ultimately stabilized FoxP3 expression and facilitated Treg cell differentiation. In NSCLC PDO models, pharmacological inhibition of glutamine metabolism reversed the immunosuppressive T cell phenotype and efficiently suppressed PDO growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>NSCLC CSCs mediate TME immunosuppression via a glutamine metabolism-dependent regulatory axis. Exosomal ROS-initiated FoxP3 post-translational modification is a novel mechanism underlying CSC-driven Treg differentiation. This study reveals an unreported immune evasion pathway in NSCLC and identifies glutamine metabolism as a viable therapeutic target for overcoming tumor immunosuppression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1961819","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:26:35Z","timestamp":1789446395000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiyu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Jilin University","place":["Changchun, 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