{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:48:31Z","timestamp":1792514911607,"version":"4.5.0"},"reference-count":52,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                    <jats:p\/>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Melatonin is a pineal-derived neuroendocrine hormone with pleiotropic actions on tumor biology and immune regulation. Although exogenous melatonin has been reported to exert antitumor and immunomodulatory effects, whether these actions depend on an intact endogenous pineal melatonin background remains unclear. In particular, the role of endogenous melatonin in conditioning chemokine-mediated antitumor effects has not been defined. A male mouse gastric cancer model was used to investigate the interplay between endogenous and exogenous melatonin in tumor growth, immune infiltration, and chemokine signaling. Tumor and immune tissues were analyzed by flow cytometry, immunofluorescence, RT-qPCR, and western blotting. In vitro assays evaluated the direct effects of melatonin on chemokine expression in gastric cancer cells. Exogenous melatonin suppressed tumor growth in vivo and inhibited tumor cell proliferation in vitro. These effects were accompanied by increased intratumoral CD8+ T-cell accumulation and activation of the IFN-\u03b3\u2013CXCL9\/10\u2013CXCR3 axis within tumor tissues. Pinealectomy alone did not significantly alter baseline tumor progression, but it attenuated the tumor and chemokine responses to exogenous melatonin and disturbed splenic immune homeostasis. In gastric cancer cells, melatonin directly induced CXCL9 and CXCL10 expression, indicating that tumor cells contribute to endocrine-responsive chemokine amplification. Endogenous pineal melatonin contributes to optimal responsiveness to exogenous melatonin in this gastric cancer model. It provides a critical endocrine context for effective chemokine-mediated immune modulation by exogenous melatonin. By enhancing intratumoral immune cell recruitment while preserving immune homeostasis, melatonin integrates neuroendocrine and immune regulation to suppress tumor growth.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/joe-26-0238","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:54:07Z","timestamp":1791467647000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":0,"title":["Pineal melatonin modulates responsiveness to exogenous melatonin via the IFN-\u03b3\u2013CXCL9\/10\u2013CXCR3 axis in gastric cancer"],"prefix":"10.1530","volume":"271","author":[{"given":"Xiurong","family":"Wang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]},{"name":"Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University 2 , ,","place":["Fuzhou, China"]},{"name":"Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University 3 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyi","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]},{"name":"Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University 3 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxuan","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]},{"name":"Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University 3 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rixiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of Fujian Medical University 4 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]},{"name":"Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University 2 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University 1 , ,","place":["Fuzhou, China"]},{"name":"Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University 3 , ,","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"2026102012365015500_bib1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/jpi.12075","article-title":"The role of melatonin in the cells of the innate immunity: a review","volume":"55","author":"Calvo","year":"2013","journal-title":"J Pineal Res"},{"key":"2026102012365015500_bib2","doi-asserted-by":"crossref","DOI":"10.1111\/jpi.12370","article-title":"Cancer metastasis: mechanisms of inhibition by melatonin","volume":"62","author":"Su","year":"2017","journal-title":"J Pineal Res"},{"key":"2026102012365015500_bib3","doi-asserted-by":"crossref","DOI":"10.3390\/ijms222212143","article-title":"Possible role of pineal and extra-pineal melatonin in surveillance, immunity, and first-line defense","volume":"22","author":"Markus","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026102012365015500_bib4","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1210\/er.2018-00084","article-title":"Melatonin as a hormone: new physiological and clinical insights","volume":"39","author":"Cipolla-Neto","year":"2018","journal-title":"Endocr Rev"},{"key":"2026102012365015500_bib5","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2021.107984","article-title":"Immunomodulation: an immune regulatory mechanism in carcinoma therapeutics","volume":"99","author":"Alsaffar","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"2026102012365015500_bib6","article-title":"Melatonin enhances anti-tumor immunity by targeting macrophages PD-L1 via exosomes derived from gastric cancer cells","volume":"568\u2013569","author":"Wang","year":"2023","journal-title":"Mol Cell Endocrinol"},{"key":"2026102012365015500_bib7","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/ar.21361","article-title":"Role of CD4+CD25+ regulatory T cells in melatonin-mediated inhibition of murine gastric cancer cell growth in vivo and in vitro","volume":"294","author":"Liu","year":"2011","journal-title":"Anat Rec"},{"key":"2026102012365015500_bib8","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1002\/ar.22689","article-title":"Growth-inhibitory activity of melatonin on murine foregastric carcinoma cells in vitro and the underlying molecular mechanism","volume":"296","author":"Xu","year":"2013","journal-title":"Anat Rec"},{"key":"2026102012365015500_bib9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","article-title":"CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation - a target for novel cancer therapy","volume":"63","author":"Tokunaga","year":"2018","journal-title":"Cancer Treat Rev"},{"key":"2026102012365015500_bib10","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0128757","article-title":"Effect of JAK inhibitors on release of CXCL9, CXCL10 and CXCL11 from human airway epithelial cells","volume":"10","author":"Fenwick","year":"2015","journal-title":"PLoS One"},{"key":"2026102012365015500_bib11","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1681\/ASN.2015020203","article-title":"CXCR3+ regulatory T cells control TH1 responses in crescentic GN","volume":"27","author":"Paust","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"2026102012365015500_bib12","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nri.2017.49","article-title":"Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy","volume":"17","author":"Nagarsheth","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"2026102012365015500_bib13","doi-asserted-by":"crossref","first-page":"952","DOI":"10.3389\/fimmu.2020.00952","article-title":"Beyond cell motility: the expanding roles of chemokines and their receptors in malignancy","volume":"11","author":"Morein","year":"2020","journal-title":"Front Immunol"},{"key":"2026102012365015500_bib14","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.yexcr.2010.12.017","article-title":"CXCR3 in T cell function","volume":"317","author":"Groom","year":"2011","journal-title":"Exp Cell Res"},{"key":"2026102012365015500_bib15","doi-asserted-by":"crossref","first-page":"976","DOI":"10.3389\/fimmu.2020.00976","article-title":"CXCR3 ligands in cancer and autoimmunity, chemoattraction of effector T cells, and beyond","volume":"11","author":"Karin","year":"2020","journal-title":"Front Immunol"},{"key":"2026102012365015500_bib16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: the cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"2026102012365015500_bib17","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1084\/jem.178.3.1057","article-title":"IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo","volume":"178","author":"Luster","year":"1993","journal-title":"J Exp Med"},{"key":"2026102012365015500_bib18","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1158\/0008-5472.CAN-08-2915","article-title":"Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells \u2013 significant roles of CXCL10","volume":"69","author":"Fujita","year":"2009","journal-title":"Cancer Res"},{"key":"2026102012365015500_bib19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00262-014-1629-5","article-title":"CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo","volume":"64","author":"Wennerberg","year":"2015","journal-title":"Cancer Immunol Immunother"},{"key":"2026102012365015500_bib20","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1309\/4EJ9KL7CGDENVVLE","article-title":"Type I interferon\u2013associated recruitment of cytotoxic lymphocytes: a common mechanism in regressive melanocytic lesions","volume":"124","author":"Wenzel","year":"2005","journal-title":"Am J Clin Pathol"},{"key":"2026102012365015500_bib21","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1158\/1541-7786.MCR-18-0114","article-title":"Digital PCR-based T-cell quantification\u2013assisted deconvolution of the microenvironment reveals that activated macrophages drive tumor inflammation in uveal melanoma","volume":"16","author":"de Lange","year":"2018","journal-title":"Mol Cancer Res"},{"key":"2026102012365015500_bib22","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1097\/CJI.0b013e3181fb045d","article-title":"Interferons induce CXCR3-cognate chemokine production by human metastatic melanoma","volume":"33","author":"Dengel","year":"2010","journal-title":"J Immunother"},{"key":"2026102012365015500_bib23","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1002\/(SICI)1096-9896(199912)189:4<552::AID-PATH469>3.0.CO;2-I","article-title":"Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma","volume":"189","author":"Kunz","year":"1999","journal-title":"J Pathol"},{"key":"2026102012365015500_bib24","doi-asserted-by":"crossref","first-page":"23169","DOI":"10.1074\/jbc.273.36.23169","article-title":"The \u03b1-chemokine, stromal cell-derived factor-1\u03b1, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways","volume":"273","author":"Ganju","year":"1998","journal-title":"J Biol Chem"},{"key":"2026102012365015500_bib25","doi-asserted-by":"crossref","first-page":"7458","DOI":"10.1038\/ncomms8458","article-title":"Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints","volume":"6","author":"Mikucki","year":"2015","journal-title":"Nat Commun"},{"key":"2026102012365015500_bib26","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1158\/0008-5472.CAN-08-2281","article-title":"Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment","volume":"69","author":"Harlin","year":"2009","journal-title":"Cancer Res"},{"key":"2026102012365015500_bib27","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.3390\/nu13103577","article-title":"Melatonin prevents T lymphocyte infiltration to the kidneys of hypertensive rats, induced by a high-salt diet, by preventing the expression of CXCR3 ligand chemokines","volume":"13","author":"Bier","year":"2021","journal-title":"Nutrients"},{"key":"2026102012365015500_bib28","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.668002","article-title":"An integrative transcriptomic and metabolomic study revealed that melatonin plays a protective role in chronic lung inflammation by reducing necroptosis","volume":"12","author":"Mao","year":"2021","journal-title":"Front Immunol"},{"key":"2026102012365015500_bib29","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.biopha.2010.09.006","article-title":"Pharmacologic concentrations of melatonin have diverse influence on differential expressions of angiogenic chemokine genes in different hepatocellular carcinoma cell lines","volume":"64","author":"Lin","year":"2010","journal-title":"Biomed Pharmacother"},{"key":"2026102012365015500_bib30","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.trecan.2024.03.008","article-title":"Gastric cancer immunosuppressive microenvironment heterogeneity: implications for therapy development","volume":"10","author":"Yasuda","year":"2024","journal-title":"Trends Cancer"},{"key":"2026102012365015500_bib31","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1038\/s41467-022-32570-z","article-title":"Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment","volume":"13","author":"Chen","year":"2022","journal-title":"Nat Commun"},{"key":"2026102012365015500_bib32","article-title":"Clinical significance of the tumor microenvironment on immune tolerance in gastric cancer","volume":"16","author":"He","year":"2025","journal-title":"Front Immunol"},{"key":"2026102012365015500_bib33","doi-asserted-by":"crossref","DOI":"10.1016\/j.lfs.2019.117191","article-title":"Effect of melatonin on T\/B cell activation and immune regulation in pinealectomy mice","volume":"242","author":"Luo","year":"2020","journal-title":"Life Sci"},{"key":"2026102012365015500_bib34","doi-asserted-by":"crossref","DOI":"10.1111\/jpi.12394","article-title":"Melatonin signaling in T cells: functions and applications","volume":"62","author":"Ren","year":"2017","journal-title":"J Pineal Res"},{"key":"2026102012365015500_bib35","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41416-020-01048-4","article-title":"Cytotoxic CD8+ T cells in cancer and cancer immunotherapy","volume":"124","author":"Raskov","year":"2021","journal-title":"Br J Cancer"},{"key":"2026102012365015500_bib36","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.3892\/ol.2020.11828","article-title":"CD8(+) T cells located in tertiary lymphoid structures are associated with improved prognosis in patients with gastric cancer","volume":"20","author":"Li","year":"2020","journal-title":"Oncol Lett"},{"key":"2026102012365015500_bib37","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.5114\/aoms.2019.86101","article-title":"Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis and experimental validation","volume":"16","author":"Zhang","year":"2020","journal-title":"Arch Med Sci"},{"key":"2026102012365015500_bib38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41417-021-00303-x","article-title":"Key chemokines direct migration of immune cells in solid tumors","volume":"29","author":"Kohli","year":"2022","journal-title":"Cancer Gene Ther"},{"key":"2026102012365015500_bib39","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/cr.2016.50","article-title":"MYC \u2013 a thorn in the side of cancer immunity","volume":"26","author":"Spranger","year":"2016","journal-title":"Cell Res"},{"key":"2026102012365015500_bib40","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/s42003-021-02004-5","article-title":"ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance","volume":"4","author":"Jang","year":"2021","journal-title":"Commun Biol"},{"key":"2026102012365015500_bib41","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41568-023-00635-w","article-title":"How chemokines organize the tumour microenvironment","volume":"24","author":"Mempel","year":"2024","journal-title":"Nat Rev Cancer"},{"key":"2026102012365015500_bib42","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.immuni.2021.01.012","article-title":"Chemokines and the immune response to cancer","volume":"54","author":"Ozga","year":"2021","journal-title":"Immunity"},{"key":"2026102012365015500_bib43","doi-asserted-by":"crossref","first-page":"R921","DOI":"10.1016\/j.cub.2020.06.081","article-title":"The tumor microenvironment","volume":"30","author":"Anderson","year":"2020","journal-title":"Curr Biol"},{"key":"2026102012365015500_bib44","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2174\/1874609811306010016","article-title":"Age-related decline in melatonin and its MT1 receptor are associated with decreased sensitivity to melatonin and enhanced mammary tumor growth","volume":"6","author":"Hill","year":"2013","journal-title":"Curr Aging Sci"},{"key":"2026102012365015500_bib45","doi-asserted-by":"crossref","first-page":"8806","DOI":"10.3390\/ijms21228806","article-title":"Thymus-pineal gland axis: revisiting its role in human life and ageing","volume":"21","author":"Rezzani","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2026102012365015500_bib46","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1056\/NEJMra1703481","article-title":"Immune-related adverse events associated with immune checkpoint blockade","volume":"378","author":"Postow","year":"2018","journal-title":"N Engl J Med"},{"key":"2026102012365015500_bib47","doi-asserted-by":"crossref","first-page":"3779","DOI":"10.3390\/ijms23073779","article-title":"Use of melatonin in cancer treatment: where are we?","volume":"23","author":"Wang","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2026102012365015500_bib48","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1615\/CritRevOncog.v13.i4.30","article-title":"Light at night, chronodisruption, melatonin suppression, and cancer risk: a review","volume":"13","author":"Reiter","year":"2007","journal-title":"Crit Rev Oncog"},{"key":"2026102012365015500_bib49","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0065-2776(07)96002-2","article-title":"Regulation of interferon-gamma during innate and adaptive immune responses","volume":"96","author":"Schoenborn","year":"2007","journal-title":"Adv Immunol"},{"key":"2026102012365015500_bib50","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.3390\/cancers13133225","article-title":"Immune circuits to shape natural killer cells in cancer","volume":"13","author":"Mattiola","year":"2021","journal-title":"Cancers"},{"key":"2026102012365015500_bib51","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1159\/000109107","article-title":"Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of rats","volume":"6","author":"Bubenik","year":"1997","journal-title":"Biol Signals"},{"key":"2026102012365015500_bib52","first-page":"262","article-title":"Persistence of circadian rhythms of melatonin and N-acetylserotonin in the serum of rats after pinealectomy","volume":"32","author":"Yu","year":"1981","journal-title":"Neuroendocrinology"}],"container-title":["Journal of Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.bioscientifica.com\/joe\/article-pdf\/doi\/10.1530\/JOE-26-0238\/526335\/joe-26-0238.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/joe\/article-pdf\/doi\/10.1530\/JOE-26-0238\/526335\/joe-26-0238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:37:05Z","timestamp":1792514225000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/joe\/article\/271\/1\/e260238\/78353\/Pineal-melatonin-modulates-responsiveness-to"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,10,1]]}},"URL":"https:\/\/doi.org\/10.1530\/joe-26-0238","relation":{},"ISSN":["0022-0795","1479-6805"],"issn-type":[{"value":"0022-0795","type":"print"},{"value":"1479-6805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"e260238"}}