{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:51:20Z","timestamp":1782399080522,"version":"3.54.5"},"reference-count":33,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"unspecified","delay-in-days":24,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81672280"],"award-info":[{"award-number":["81672280"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81874110"],"award-info":[{"award-number":["81874110"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Invigorating Health Care through Science, Technology and Education","award":["ZDXM2024002"],"award-info":[{"award-number":["ZDXM2024002"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,8]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Understanding resistance to anti-programmed cell death protein 1 (PD-1) therapy is critical for developing reversal strategies. Although ectonucleotidase CD39 (ENTPD1) (CD39)\n                      <jats:sup>+<\/jats:sup>\n                      cluster of differentiation 8 (CD8)\n                      <jats:sup>+<\/jats:sup>\n                      T cells have been associated with antitumor responses, the na\u00efve regional distribution of these cells and their dysregulated dynamics as determinants of response or resistance to anti-PD-1 monoclonal antibody (mAb) therapy remain poorly characterized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed targeted biopsy techniques to characterize the spatial infiltration of CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells within the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). It was further performed independent NSCLC cohort, flow cytometry, multiplex immunohistochemistry, single-cell RNA sequencing and functional studies to investigate these cells in vitro and in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Region-specific CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells located outside hypoxic zones initially served as potential biomarkers to predict response to anti-PD-1 therapy. However, hypoxia gradients within the TME were associated with regional depletion of these cells in NSCLC. Subsequently, anti-PD-1 mAb treatment further reduced intratumoral CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell levels, even in the context of improved oxygenation following tumor regression, suggesting a feedback mechanism modulating antitumor immunity. Multiple assays revealed that the absence of CD39 impaired functional restoration of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells on PD-1 blockade. This finding was corroborated by distinct transcriptional profiles, enhanced cytotoxic\/effector signatures, and a more oligoclonal and expanded T-cell receptor (TCR) repertoire in CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells across the CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell differentiation continuum.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings identify CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells as an important regulator of anti-PD-1 therapy, whereas initial hypoxia followed by anti-PD-1 treatment sequentially shapes tumor-regional localization of these cells, ultimately linking to suboptimal immunotherapeutic responses.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-014940","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:25:19Z","timestamp":1782397519000},"page":"e014940","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Sequential involvement of hypoxia and anti-PD-1 treatment in shaping tumor-regional CD39\n                    <sup>+<\/sup>\n                    CD8\n                    <sup>+<\/sup>\n                    T cells highlights immunotherapy-resistant features in NSCLC"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3114-0272","authenticated-orcid":false,"given":"Jiajuan","family":"Wu","sequence":"first","affiliation":[{"name":"Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, 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