{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:43:58Z","timestamp":1792799038921,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"unspecified","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Young Science and Technology Talents Lifting Project of Jiangsu Association for Science and Technology","award":["JSTJ-2023-WJ017"],"award-info":[{"award-number":["JSTJ-2023-WJ017"]}],"id":[{"id":"https:\/\/ror.org\/019t77f77","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Excellent Young Scientists Fund Cultivation Project of the National Natural Science Foundation of Nanjing Drum Tower Hospital","award":["Nanjing Drum Tower Hospital-2024-JCYJ-YP-04"],"award-info":[{"award-number":["Nanjing Drum Tower Hospital-2024-JCYJ-YP-04"]}],"id":[{"id":"https:\/\/ror.org\/026axqv54","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473117, 82373068"],"award-info":[{"award-number":["82473117, 82373068"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Outstanding Young Scientist Fund of the Nanjing Health Science and Technology Development Program","award":["JQX23005"],"award-info":[{"award-number":["JQX23005"]}]},{"name":"Key Program of Nanjing Commission of Health","award":["ZKX22064"],"award-info":[{"award-number":["ZKX22064"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,10,6]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Despite progress in immunotherapy for several solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive, primarily due to its profoundly immunosuppressive tumor microenvironment (TME) characterized by limited CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration. Novel strategies are needed to overcome this immune resistance and enhance the efficacy of checkpoint blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established a patient-derived organoid (PDO)-autologous T cell co-culture platform using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens from patients with PDAC unresponsive to anti-programmed cell death protein-1 (PD-1) therapy. This high-throughput system was used to screen a focused library of epigenetic compounds. The effects of candidate drugs were validated in orthotopic PDAC models, integrating functional assays, sequencing analyses, and patient data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Through screening, we identified the histone demethylase inhibitor JIB04, which synergized with anti-PD-1 therapy to enhance T cell cytotoxicity in PDO-T cell co-cultures. Mechanistically, JIB04 suppressed nuclear-factor-E2-related factor 2 (Nrf2) and reduced chromatin accessibility at distal regulatory regions of its downstream target solute carrier family 40 member 1 (Slc40a1), impairing iron efflux and promoting ferroptosis in tumor cells. This ferroptotic stress facilitated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration and activation, thereby converting the PDAC TME from \u201ccold\u201d to \u201chot.\u201d Patients with PDAC with lower Nrf2 and Slc40a1 expression exhibited higher CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration and improved responses to anti-PD-1 therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings establish a PDO-T cell platform for precision immunotherapy screening and identify JIB04 as a promising epigenetic agent that induces ferroptosis and sensitizes PDAC to immune checkpoint blockade. This ferroptosis-based reprogramming provides a potential strategy to overcome resistance and improve clinical outcomes in PDAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013269","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T06:15:16Z","timestamp":1761286516000},"page":"e013269","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Epigenetic suppression of Nrf2\u2013Slc40a1 axis induces ferroptosis and enhances immunotherapy in pancreatic cancer"],"prefix":"10.1136","volume":"13","author":[{"given":"Yixuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranran","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of 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