{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:04:36Z","timestamp":1789362276057,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Advanced melanoma remains a major clinical challenge due to resistance to immune checkpoint inhibitors (ICIs, e.g., anti PD-1). Astragalus Polysaccharide (APS) is a clinically approved immunomodulator for cancer treatment. However, its interaction with anti PD-1 remains largely unknown. This study aims to explore the efficacy and underlying mechanism of APS combined with anti PD-1 in melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      For\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies, the anti-tumor effect of APS combined with anti PD-1 was evaluated in a B16-OVA melanoma mouse model. For mechanism exploration, immunohistochemistry, flow cytometry, ELISA, PCR array, qRT-PCR, Western blotting and confocal microscopy were employed to detect tumor immune microenvironment changes and related signaling pathway activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Unexpectedly, APS significantly antagonized the anti-tumor efficacy of anti PD-1 in melanoma mice. APS reversed anti PD-1-induced infiltration of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and dendritic cells (DCs) in the tumor microenvironment, and impaired DC maturation and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell activation. Mechanistically, APS significantly inhibited JAK-STAT1 signaling, downregulated MHCII master regulator CIITA, and subsequently reduced MHCII expression. Meanwhile, APS markedly suppressed TLR signaling and attenuated NF-\u03baB mediated inflammatory responses in B16-OVA melanoma cells and DCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>APS antagonized anti PD-1 efficacy by inducing an immunosuppressive microenvironment via dual inhibition of JAK-STAT1\/CIITA signaling and TLR\/NF-\u03baB signaling. This study suggests that the combination of natural polysaccharides and ICIs may warrant caution, although further studies are needed to validate these findings and determine their clinical relevance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1947786","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:37:45Z","timestamp":1789360665000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Astragalus polysaccharide antagonized anti PD-1 efficacy in melanoma through inhibiting JAK-STAT1\/CIITA and TLR\/NF-\u03baB signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Ruilong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinshu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Nantong Haimen People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Chuxiong Autonomous Prefecture Hospital of Traditional Chinese Medicine","place":["Chuxiong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Integrative Medicine, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Li","sequence":"additional","affiliation":[{"name":"Suzhou Medical College of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiochon","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2019.1640032","article-title":"Current state of melanoma diagnosis and treatment","volume":"20","author":"Davis","year":"2019","journal-title":"Cancer Biol Ther"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13010225","article-title":"Advances in immunotherapy and targeted therapy of Malignant melanoma","volume":"13","author":"Wang","year":"2025","journal-title":"Biomedicines"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.052","article-title":"Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth","volume":"162","author":"Kleffel","year":"2015","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4110\/in.2023.23.e41","article-title":"The role of CD4 T cell help in CD8 T cell differentiation and function during chronic infection and cancer","volume":"23","author":"Topchyan","year":"2023","journal-title":"Immune Netw"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.08.002","article-title":"Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment","volume":"59","author":"Marzagalli","year":"2019","journal-title":"Semin Cancer Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2023.102330","article-title":"Major histocompatibility complex class II in the tumor microenvironment: functions of nonprofessional antigen-presenting cells","volume":"83","author":"Maccy","year":"2023","journal-title":"Curr Opin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10582","article-title":"Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1\/PD-L1 therapy","volume":"7","author":"Johnson","year":"2016","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/s0171-2985(11)80550-4","article-title":"Regulation of MHC class II gene expression by the class II transactiva tor","volume":"5","author":"Reith","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)80468-9","article-title":"Activation of the MHC class II transactivator CIITA by interferon-\u03b3 requires cooperative interaction between Stat1 and USF-1","volume":"8","author":"Muhlethaler-Mottet","year":"1998","journal-title":"Immunity"},{"key":"B10","doi-asserted-by":"publisher","first-page":"7165","DOI":"10.1038\/s41467-024-51496-2","article-title":"Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade","volume":"15","author":"Holzgruber","year":"2024","journal-title":"Nat Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01081","article-title":"HLA-class II artificial antigen presenting cells in CD4+ T cell-based immunotherapy","volume":"10","author":"Couture","year":"2019","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.812774","article-title":"Toll-like receptor signaling and its role in cell-mediated immunity","volume":"13","author":"Duan","year":"2022","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.medidd.2022.100122","article-title":"The critical role of toll-like receptor-mediated signaling in cancer immunotherapy","volume":"14","author":"Chen","year":"2022","journal-title":"Med Drug Discov"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1274048","article-title":"Natural polysaccharides exert anti-tumor effects as dendritic cell immune enhancers","volume":"13","author":"Xiong","year":"2023","journal-title":"Front Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/foods13233882","article-title":"The influence and mechanisms of natural plant polysaccharides on intestinal microbiota-mediated metabolic disorders","volume":"13","author":"Chen","year":"2024","journal-title":"Foods"},{"key":"B16","doi-asserted-by":"publisher","first-page":"99","DOI":"10.4103\/jcrp.jcrp_3_20","article-title":"Immuno-potentiating effects of Astragalus polysaccharides: a mini-literature review","volume":"7","author":"Chen","year":"2020","journal-title":"J Cancer Res Pract"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1186\/s12885-024-12788-4","article-title":"Modulation of PD-L1 by Astragalus polysaccharide attenuates the induction of melanoma stem cell properties and overcomes immune evasion","volume":"24","author":"Yu","year":"2024","journal-title":"BMC Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1177\/1559325816685182","article-title":"Therapeutic effect of Astragalus polysaccharides on hepatocellular carcinoma H22-bearing mice","volume":"15","author":"Liu","year":"2017","journal-title":"Dose Response"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v18.i47.7079","article-title":"Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice","volume":"18","author":"Tian","year":"2012","journal-title":"World J Gastroenterol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/jci152864","article-title":"Tim-3 mediates T cell trogocytosis to limit antitumor immunity","volume":"132","author":"Pangiao","year":"","journal-title":"J Clin Invest"},{"key":"B21","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s40425-018-0361-7","article-title":"Radiation therapy and PD-1\/PD-L1 blockade: the clinical development of an evolving anticancer combination","volume":"6","author":"Gong","year":"2018","journal-title":"J Immunother Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s41698-023-00362-3","article-title":"Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade","volume":"7","author":"Fox","year":"2023","journal-title":"NPJ Precis Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11071169","article-title":"Development and optimal immune strategy of an alum-stabilized Pickering emulsion for cancer vaccines","volume":"11","author":"Peng","year":"2023","journal-title":"Vaccines"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.119966","article-title":"Astragalus injection antagonizes the efficacy of anti-PD-1 against melanoma through down-regulating MHC-II expression","volume":"349","author":"Lei","year":"2025","journal-title":"J Ethnopharmacol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2021.1890411","article-title":"TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL","volume":"13","author":"Malik-Chaudhry","year":"","journal-title":"mAbs"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93397","article-title":"Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer","volume":"2","author":"Sato-Kaneko","year":"2017","journal-title":"JCI Insight"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-18-0280","article-title":"SD-101 in combination with pembrolizumab in advanced melanoma: results of a phase Ib, multicenter study","volume":"8","author":"Ribas","year":"2018","journal-title":"Cancer Discov"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1604958","article-title":"Mutations associated with acquired resistance to PD-1 blockade in melanoma","volume":"375","author":"Zaretsky","year":"2016","journal-title":"N Engl J Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.04.031","article-title":"Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression","volume":"19","author":"Garcia-Diaz","year":"2017","journal-title":"Cell Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rraf021","article-title":"Investigating tumor immunogenicity as a determinant of differential abscopal effects","volume":"66","author":"Jeong","year":"2025","journal-title":"J Radiat Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.115150","article-title":"Defective removal of invariant chain peptides from MHC class II suppresses tumor antigen presentation and promotes tumor growth","volume":"44","author":"Bandola-Simon","year":"2025","journal-title":"Cell Rep"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.22.13.4781-4791.2002","article-title":"Kinetics of a gamma interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation","volume":"22","author":"Morris","year":"2002","journal-title":"Mol Cell Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1007\/s00262-024-03679-5","article-title":"TLR5 agonist in combination with anti-PD-1 treatment enhances anti-tumor effect through M1\/M2 macrophage polarization shift and CD8(+) T cell priming","volume":"73","author":"Lee","year":"2024","journal-title":"Cancer Immunol Immunother"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0465-0","article-title":"Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses","volume":"17","author":"Hilligan","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1232456","article-title":"Editorial: Natural products modulate the sensitivity of cancer to anti-PD-1 based immunotherapy","volume-title":"Frontiers in Pharmacology","author":"Chamcheu","year":"2023"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1168226","article-title":"Traditional Chinese medicine inhibits PD-1\/PD-L1 axis to sensitize cancer immunotherapy: a literature review","volume":"13","author":"Zheng","year":"2023","journal-title":"Front Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2018.1539614","article-title":"Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity","volume":"8","author":"Kokolus","year":"2019","journal-title":"Oncoimmunology"},{"key":"B38","article-title":"Determination of polysaccharide content in Astragalus oral liquid and injection by phenol-sulfuric acid method","volume":"29","author":"Chen","year":"2015","journal-title":"Res Pract Chin Medicines"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/cbdv.202403031","article-title":"Advances in the preparation and bioactivity of polysaccharides from medicinal plants with different molecular weights: a review","volume":"22","author":"Fan","year":"2025","journal-title":"Chem Biodivers"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202048966","article-title":"Tumor infiltrated immune cell types support distinct immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer","volume":"51","author":"Ku","year":"2021","journal-title":"Eur J Immunol"},{"key":"B41","article-title":"Interferon gamma stimulates cellular maturation of dendritic cell line DC2.4 leading to induction of efficient cytotoxic T cell responses and antitumor immunity","volume":"4","author":"He","year":"2007","journal-title":"Cell Mol Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900778","article-title":"Cancer cell\u2013intrinsic expression of MHC class II regulates the immune microenvironment and response to anti\u2013PD-1 therapy in lung adenocarcinoma","volume":"204","author":"Johnson","year":"2020","journal-title":"J Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801480","article-title":"In primitive zebrafish, MHC class II expression is regulated by IFN-\u03b3, IRF1, and two forms of CIITA","volume":"204","author":"Hou","year":"2020","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-006-0275-y","article-title":"Tumor cells prevent mouse dendritic cell maturation induced by TLR ligands","volume":"56","author":"Idoyaga","year":"2007","journal-title":"Cancer Immunol Immunother"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1947786\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:37:56Z","timestamp":1789360676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1947786\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2026.1947786"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1947786","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]},"article-number":"1947786"}}