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Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>\n                    Metal ions are increasingly recognized as regulators of immune function, yet their application in cancer immunotherapy remains underexplored. Here, we identified cobalt ions (Co\n                    <jats:sup>2+<\/jats:sup>\n                    ) as potent suppressors of IFN-\u03b3\u2013induced IDO1 expression through systematic screening of biologically relevant metal ions. Across multiple cancer cell lines, Co\n                    <jats:sup>2+<\/jats:sup>\n                    notably reduced IDO1 expression and kynurenine production. Mechanistically, Co\n                    <jats:sup>2+<\/jats:sup>\n                    destabilized IFNGR1 and inhibited IFN-\u03b3\u2013JAK\u2013STAT1 signaling, thereby restoring kynurenine\/tryptophan metabolic balance and alleviating immunosuppression of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell. These effects reprogrammed the immunosuppressive tumor microenvironment toward enhanced cytotoxic T cell activity. To minimize the toxicity associated with free Co\n                    <jats:sup>2+<\/jats:sup>\n                    , we developed ConaHA, a hyaluronic acid\u2013based nanoparticle platform enabling sustained and tumor-targeted cobalt delivery. ConaHA enhanced cobalt-mediated immune checkpoint blockade in vivo, resulting in notably improved antitumor efficacy in subcutaneous Panc02, MC38, and B16F10 tumor models and KPC (\n                    <jats:italic toggle=\"yes\">LSL-Kras<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic toggle=\"yes\">G12D\/+<\/jats:italic>\n                    <\/jats:sup>\n                    ;\n                    <jats:italic toggle=\"yes\">LSL-Trp53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic toggle=\"yes\">R172H\/+<\/jats:italic>\n                    <\/jats:sup>\n                    ;\n                    <jats:italic toggle=\"yes\">Pdx-1-Cre<\/jats:italic>\n                    ) models. Collectively, these findings reveal a previously unrecognized immunoregulatory role of Co\n                    <jats:sup>2+<\/jats:sup>\n                    and establish a promising framework for metalloimmunotherapy through modulation of metal-immune signaling pathways.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg6398","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:04:04Z","timestamp":1789754644000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Cobalt-mediated suppression of IFN-\u03b3\u2013JAK\u2013STAT1 signaling reprograms IDO1-driven immunosuppression for metalloimmunotherapy"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7270-7366","authenticated-orcid":true,"given":"Tianyi","family":"Jiang","sequence":"first","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9701-0855","authenticated-orcid":true,"given":"Xiaowan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4531-476X","authenticated-orcid":true,"given":"Zhixin","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulinaizaier","family":"Abudusaimaiti","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Song","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6743-941X","authenticated-orcid":true,"given":"Hongtao","family":"Duan","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4622-7755","authenticated-orcid":true,"given":"Yaoxu","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Du","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7452-2467","authenticated-orcid":true,"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieying","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6465-7488","authenticated-orcid":true,"given":"Yunjiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China."},{"name":"National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, Guangdong 511442, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.07.012"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01111-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.01.035"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93433"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2019-000510"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.14"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.09.002"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.031"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.022"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.04.031"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.016"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09666"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2012.09.006"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0016-5"},{"key":"e_1_3_2_16_2","first-page":"673","article-title":"Cancer 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