{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:54:27Z","timestamp":1790970867276,"version":"4.1.0"},"reference-count":49,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"unspecified","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Basic and Clinical Collaborative Research Enhancement Project of Anhui Medical University","award":["2023xkjT039"],"award-info":[{"award-number":["2023xkjT039"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82300669"],"award-info":[{"award-number":["82300669"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Research Project of Anhui Province","award":["AHWJ2023A10025"],"award-info":[{"award-number":["AHWJ2023A10025"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,20]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Resistance to anti-programmed cell death protein-1 (PD-1) treatment in gastric cancer (GC) is closely associated with an immunosuppressive tumor microenvironment. However, the role of neutrophils in resistance to anti-PD-1 therapy remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing was performed on tumor samples from patients with advanced GC receiving anti-PD-1 therapy to identify neutrophil subsets associated with neutrophil extracellular traps (NETs). Multilevel experimental validation was conducted using multiomics analysis, flow cytometry, multiplex immunofluorescence, and in vitro co-culture. Therapeutic strategies targeting NETs and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell exhaustion were evaluated in a mouse model of YTN16 tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a NETs-associated neutrophil subset enriched in patients with GC resistant to anti-PD-1 treatment. This subset was marked by CD177, and it exhibited a high potential for NETs release. Peripheral blood NETs levels and CD177\n                      <jats:sup>+<\/jats:sup>\n                      neutrophil ratios in patients with GC act as markers for evaluating the efficacy of PD-1 inhibitors. Furthermore, transforming growth factor-\u03b21 (TGF-\u03b21), which was highly expressed in GC and spatially colocalized with CD177\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils, might induce neutrophils to release NETs via the Smad3-NFE2 axis. NETs promoted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion by activating the MEK\/ERK-c-Fos\/JunB axis, as evidenced by increased PD-1\/TIM3 expression and reduced interferon-gamma\/tumor necrosis factor-alpha secretion. In vivo experiments confirmed that targeted inhibition of NETs formation using DNase I or TGF-\u03b21 inhibitors significantly suppressed tumor growth and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion. Notably, the MEK inhibitor trametinib reversed the immunosuppressive microenvironment associated with CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion and synergistically enhanced the antitumor efficacy with anti-PD-1 therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      TGF-\u03b21 drives CD177\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils to release NETs, which induce CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion via the ERK-c-Fos-JunB pathway, thereby mediating resistance to anti-PD-1 treatment in GC. Furthermore, targeting NETs formation and combining trametinib with PD-1 inhibitors can significantly reverse CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion, exert synergistic antitumor effects, and offer a potential therapeutic strategy for overcoming resistance to anti-PD-1 therapy in GC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015618","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T12:10:13Z","timestamp":1785845413000},"page":"e015618","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["TGF-\u03b21 drives neutrophil extracellular traps formation to promote CD8\n                    <sup>+<\/sup>\n                    T cell exhaustion via the ERK-c-Fos-JunB axis, mediating gastric cancer immunotherapy 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