{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:53:02Z","timestamp":1790189582998,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024MD763927"],"award-info":[{"award-number":["2024MD763927"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["GZC20230334"],"award-info":[{"award-number":["GZC20230334"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973460"],"award-info":[{"award-number":["81973460"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008402","name":"Chengdu University of Traditional Chinese Medicine","doi-asserted-by":"publisher","award":["ZDZX2022002"],"award-info":[{"award-number":["ZDZX2022002"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008402","name":"Chengdu University of Traditional Chinese Medicine","doi-asserted-by":"publisher","award":["BSZ2023038"],"award-info":[{"award-number":["BSZ2023038"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Cordyceps sinensis<\/jats:italic>\n                    is a traditional medicinal fungus known for its immunomodulatory properties. Its bioactive sphingolipids (SPLs) exhibit antitumor potential, though their mechanisms remain poorly understood. This study aimed to identify the active SPLs from\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. sinensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    and investigate their synergistic effects with \u03b1PD\u20101 (anti\u2010programmed death\u20101 antibody) therapy. SPLs were isolated from\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. sinensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    via UPLC\u2013MS\/MS\u2010guided purification. The antitumor efficacy and immunomodulatory synergy with \u03b1PD\u20101 were assessed using a Lewis lung carcinoma (LLC) tumor\u2010bearing mouse model and in\u00a0vitro co\u2010culture systems. Mechanisms involving sphingosine kinase 1 (SphK1) were explored through cellular thermal shift assays, enzymatic activity tests, surface plasmon resonance, molecular docking, and molecular dynamics simulations. The combination of SPLs and \u03b1PD\u20101 enhanced antitumor immunity by promoting CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell infiltration and suppressing PD\u2010L1 expression in the tumor microenvironment. Metabolomic and transcriptomic analyses revealed that SPLs shifted the sphingolipid balance by targeting the SphK1\u2010mediated ceramide\/sphingosine\u20101\u2010phosphate (Cer\/S1P) axis, promoting antitumor immunity. A novel ceramide, cordysinamide A, was identified as a key bioactive constituent and shown to bind directly to SphK1 (IC\u2085\u2080\u2009=\u200928.45\u2009\u03bcM; KD\u2009=\u200914.4\u2009\u03bcM), stabilizing its structure and inhibiting S1P production. This shift increased IL\u20102 and IFN\u2010\u03b3 levels and sensitized tumors to \u03b1PD\u20101 treatment. This study identifies\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. sinensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    \u2010derived SPLs as key bioactive components that overcome \u03b1PD\u20101 resistance by targeting the SphK1\u2010mediated Cer\/S1P balance. Our findings propose a natural product\u2010based strategy to change immunosuppressive metabolism in non\u2010small cell lung cancer.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70234","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T07:29:31Z","timestamp":1769585371000},"page":"1696-1712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bioactive Sphingolipids of\n                    <i>Cordyceps sinensis<\/i>\n                    Modulate Tumor Immunity Through the\n                    <scp>SphK1<\/scp>\n                    \u2010Mediated Cer\/\n                    <scp>S1P<\/scp>\n                    Axis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8052-3917","authenticated-orcid":false,"given":"Qi\u2010Xuan","family":"Kuang","sequence":"first","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen\u2010Yi","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao\u2010Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Jie","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Qing","family":"Huang","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao\u2010Ran","family":"Lei","sequence":"additional","affiliation":[{"name":"School of Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan","family":"Peng","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Fang","family":"Jiang","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Fu","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da\u2010Le","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Ke","family":"Li","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng\u2010Ming","family":"You","sequence":"additional","affiliation":[{"name":"TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51495-3"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.102390"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2486-6"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.06.006"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202104452"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00551-9"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107899"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.881182"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2022.105810"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.1c01141"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00742-y"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00911-z"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01018-9"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105574"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lwt.2022.113497"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117508"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00890-4"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196576"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-024-00895-0"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adg8817"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pccm.2025.05.002"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103301"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.8b02706"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.96"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031289"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07787-1"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-024-01626-6"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2022.10.002"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr.2019.10.04"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115126"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00789-4"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/np030153a"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/14789450.2024.2406785"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-023-00798-6"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adv0558"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70234","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70234","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T04:21:53Z","timestamp":1775622113000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/ptr.70234"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70234","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"2025-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}