{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:22:35Z","timestamp":1787728955718,"version":"build-2784847793"},"reference-count":57,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82503283"],"award-info":[{"award-number":["82503283"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272737"],"award-info":[{"award-number":["82272737"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073394"],"award-info":[{"award-number":["82073394"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M761317"],"award-info":[{"award-number":["2024M761317"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic stress is increasingly recognised as a risk factor for poor prognosis in colorectal cancer (CRC) through sustained activation of the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis and sympathetic nervous system, yet the mechanisms by which psychological stress signals are transmitted from the central nervous system to the peripheral tumour immune microenvironment remain poorly understood. Brain\u2010derived small extracellular vesicles (BD\u2010sEVs), which can cross the blood\u2013brain barrier, represent potential mediators of this neuroimmune crosstalk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A chronic restraint stress (CRS) mouse model was established in both subcutaneous (MC38) and orthotopic (CT26) CRC models. BD\u2010sEVs were enriched from plasma using anti\u2010L1 cell adhesion molecule (L1CAM) antibodies and characterised by transmission electron microscopy and nanoparticle tracking analysis. Multichannel flow cytometry was used to analyse immune cell populations in the tumour microenvironment. Mechanistic studies included microRNA (miRNA) sequencing, single\u2010cell RNA sequencing, co\u2010immunoprecipitation, mass spectrometry, mitochondrial function assessment and mitochondrial DNA (mtDNA) detection. Clinical validation was performed in a retrospective cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a067) and a prospective cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a037) of CRC patients, with anxiety levels assessed by the Hamilton Anxiety Rating Scale (HAMA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We show that chronic stress\u2010activated brain regions remodel the miRNA cargo of circulating BD\u2010sEVs, which are taken up by CD4\n                      <jats:sup>+<\/jats:sup>\n                      na\u00efve T cells within the tumour microenvironment, promoting regulatory T\u2010cell (Treg) differentiation and immunosuppressive function. Mechanistically, stress\u2010responsive miRNAs (miR\u2010342\u20103p, miR\u201015a\u20105p and miR\u2010381\u20103p) upregulate phorbol\u201012\u2010myristate\u201013\u2010acetate\u2010induced protein 1 (NOXA), which directly binds the mitochondrial chaperone heat shock protein 60 (HSP60) and inhibits its chaperone activity, triggering selective mtDNA release into the cytoplasm. Cytosolic mtDNA activates the cyclic GMP\u2012AMP synthase (cGAS)\u2012stimulator of interferon genes (STING)\u2012type I interferon (IFN\u2010I) pathway, driving Treg differentiation independently of the canonical myeloid cell leukaemia 1 (MCL\u20101)\u2010dependent apoptotic pathway. Clinically, intratumoural CD4\n                      <jats:sup>+<\/jats:sup>\n                      NOXA\/Forkhead box P3 (FOXP3) expression correlates significantly with patient anxiety scores and predicts adverse survival outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study reveals an immunosuppressive \u2018chronic stress\u2012BD\u2010sEV\u2012NOXA\u2012HSP60\u2012Treg\u2019 axis and provides crucial mechanistic insights into the psychoneuroimmunological contributions to cancer progression and novel targets for therapeutic intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Chronic stress promotes the differentiation of regulatory T cells (Treg) in the tumour microenvironment through brain\u2010derived small extracellular vesicles (BD\u2010sEVs) to inhibit antitumour immunity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Mechanistically, BD\u2010sEV\u2010induced phorbol\u201012\u2010myristate\u201013\u2010acetate\u2010induced protein 1 (NOXA) binds heat shock protein 60 (HSP60) and inhibits its chaperone activity, triggering mitochondrial DNA (mtDNA) release and activation of the cyclic GMP\u2012AMP synthase (cGAS)\u2012stimulator of interferon genes (STING) pathway to drive Treg differentiation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The stress\u2012BD\u2010sEV\u2012NOXA\u2012HSP60\u2012Treg axis is a key pathway that connects psychological stress with peripheral tumour immunosuppression.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The expression of NOXA and Forkhead box P3 (FOXP3) in clinical tumour samples correlates with the level of anxiety and may serve as potential prognostic biomarkers.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70756","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T07:07:40Z","timestamp":1787296060000},"source":"Crossref","is-referenced-by-count":0,"title":["Chronic stress\u2010induced brain\u2010derived small extracellular vesicles promote colorectal cancer through Treg differentiation"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9875-5943","authenticated-orcid":false,"given":"Huanhe","family":"Ni","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Nanfang Hospital Southern Medical University  Guangzhou China"},{"name":"Department of Laboratory Ganzhou People's Hospital  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyan","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Gynaecology Ganzhou People's Hospital  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of General Surgery Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunjie","family":"Qing","sequence":"additional","affiliation":[{"name":"Department of General Surgery Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujie","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of General Surgery Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqiong","family":"Ding","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK &amp; PD Investigation for Innovative Drugs Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK &amp; PD Investigation for Innovative Drugs Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6252-713X","authenticated-orcid":false,"given":"Hui","family":"Pan","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK &amp; PD Investigation for Innovative Drugs Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Ganzhou People's Hospital  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0560-0016","authenticated-orcid":false,"given":"Dehua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Nanfang Hospital Southern Medical University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2024.10.007"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018\u2010024\u201000807\u2010z"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201024\u20100718"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102025\u2010335627"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.01.013"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.02.002"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216986"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578\u2010025\u201001420\u2010y"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202310266"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010025\u201002477\u20106"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13823"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106610"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12459"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.12.001"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018\u2010023\u201000626\u20108"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201023\u20103871"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2023.09.014"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010025\u201002176\u20100"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.98372"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.06.014"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102022\u2010005151"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423\u2010023\u201001086\u2010x"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010023\u201000965\u20107"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2320709121"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010025\u201006291\u2010y"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010025\u201002241\u20108"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12404"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001702"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70043"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571\u2010015\u20100314\u20103"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.04.011"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100881"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav4011"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100694\u2010x"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201021\u20100316"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201021\u20100683"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe6474"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.02.013"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf5464"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsgos.2024.100401"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2017.05.144"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.07.002"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202052252"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010021\u201001352\u20104"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2024.09.002"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201052170\u20103"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.014"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010021\u201001174\u20108"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010025\u201004909\u20102"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2025.01.001"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.01.011"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102022\u2010327736"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2009.05.004"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.646537"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2015.04.004"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2016.08.002"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2015.00006"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70756","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.70756","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70756","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:39:41Z","timestamp":1787726381000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.70756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":57,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/ctm2.70756"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.70756","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"article-number":"e70756"}}