{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:14:25Z","timestamp":1780920865820,"version":"3.54.1"},"reference-count":44,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"unspecified","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"The Key Incubation Project Funds of the second hospital & clinical medical school, lanzhou university","award":["2025-24-zdfy-014"],"award-info":[{"award-number":["2025-24-zdfy-014"]}]},{"name":"Scientific Research Project of Gansu Health Industry","award":["GSWSKY2025-03"],"award-info":[{"award-number":["GSWSKY2025-03"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Sciences Foundation of China","doi-asserted-by":"crossref","award":["82460500"],"award-info":[{"award-number":["82460500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cuiying Scientific Training Program for Undergraduates of The Second Hospital & Clinical Medical School","award":["CYXZPT2025-32"],"award-info":[{"award-number":["CYXZPT2025-32"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,5,21]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The efficacy of chemo-immunotherapy in gastric cancer (GC) is limited by heterogeneous resistance and the lack of predictive biomarkers. However, the molecular mechanisms underlying concurrent intrinsic chemoresistance and extrinsic immunosuppression remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed integrative analysis of single-cell RNA sequencing and bulk transcriptomic datasets from GC cohorts to identify key regulators of chemo-immunotherapy resistance. The functional role of activating transcription factor 4 (ATF4) was validated in GC cell lines, patient-derived organoids (PDOs), and patient-derived xenograft (PDX) models. Mechanistic investigations employed chromatin immunoprecipitation sequencing, RNA-seq, and multiplex immunofluorescence to elucidate the ATF4-HSPA9-DNA damage response (DDR) axis. Clinical relevance was assessed in GC patients treated with 5-fluorouracil (5-FU) monotherapy and those receiving combination 5-FU plus anti-PD-1 therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identify integrated stress-response transcription factor ATF4 as a key regulator of dual resistance. Mechanistically, ATF4 transcriptionally upregulates HSPA9 to activate the DDR, which promotes both intrinsic chemoresistance and extrinsic immunosuppression. ATF4 overexpression reduces 5-FU sensitivity and induces CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion in PDOs and PDX models. Clinically, low ATF4 expression correlates with improved survival in GC patients receiving chemo-immunotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish the ATF4-HSPA9 axis as a dual-function therapeutic target and predictive biomarker in GC chemo-immunotherapy. This axis bridges DNA damage repair-mediated chemoresistance and T cell exhaustion, providing a strategy to overcome resistance to 5-FU and PD-1 blockade.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015109","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T11:55:16Z","timestamp":1780919716000},"page":"e015109","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting ATF4 overcomes dual resistance to chemo-immunotherapy in gastric cancer by disrupting the DNA damage response"],"prefix":"10.1136","volume":"14","author":[{"given":"Huili","family":"Ye","sequence":"first","affiliation":[{"name":"Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtai","family":"Cao","sequence":"additional","affiliation":[{"name":"The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Peng","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xu","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Xia","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[{"name":"The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China"},{"name":"The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"He","sequence":"additional","affiliation":[{"name":"The Department of Medical Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhou","sequence":"additional","affiliation":[{"name":"Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Qin","sequence":"additional","affiliation":[{"name":"The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejun","family":"Ma","sequence":"additional","affiliation":[{"name":"Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ren","sequence":"additional","affiliation":[{"name":"Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haobo","family":"Han","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwen","family":"Cai","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9995-7176","authenticated-orcid":false,"given":"Long","family":"Qin","sequence":"additional","affiliation":[{"name":"Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China"},{"name":"Biobank of Tumors from Plateau of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1942-0905","authenticated-orcid":false,"given":"Zuoyi","family":"Jiao","sequence":"additional","affiliation":[{"name":"The Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China"},{"name":"Biobank of Tumors from Plateau of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"2026060804551096000_14.6.e015109.1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/hel.12339","article-title":"Gastric cancer - 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