{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:33:00Z","timestamp":1790130780672,"version":"4.0.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"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>Introduction<\/jats:title>\n                    <jats:p>Tumor cells frequently develop immune resistance through interferon-\u03b3 (IFN-\u03b3)\u2013induced PD-L1 expression, acquisition of cancer stem cell (CSC)\u2013like features, and adaptation to hypoxia within the tumor microenvironment (TME). Although IFN-\u03b3 activates both STAT1 and STAT3, how these pathways interact to regulate immune evasion under hypoxia remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using the MC38 murine colorectal cancer model and T cell\u2013tumor spheroid co-culture assays, we examined how IFN-\u03b3 signaling through STAT1 and STAT3 regulates PD-L1 expression, CSC plasticity, and cytotoxic T cell function under normoxic and hypoxic conditions. Pharmacologic inhibitors and siRNA-mediated knockdown were used to dissect pathway function. Niclosamide, an FDA-approved anthelmintic, was evaluated as a dual STAT1\/STAT3 inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IFN-\u03b3 primarily induced PD-L1 expression through STAT1 activation, whereas CSC plasticity was associated with STAT3 signaling. STAT1 and STAT3 displayed reciprocal regulation, whereby inhibition of one enhanced activation of the other. Niclosamide effectively inhibited phosphorylation of both STAT1 and STAT3, resulting in suppressed PD-L1 upregulation, reduced CSC enrichment, and partial inhibition of hypoxia-induced HIF-1\u03b1 expression. In co-culture assays, Niclosamide enhanced T cell infiltration, reduced exhaustion under hypoxic conditions, and improved T cell\u2013mediated tumor killing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify Niclosamide as a potent dual STAT1\/STAT3 inhibitor capable of reversing IFN-\u03b3\u2013 and hypoxia-driven immune evasion. Repurposing Niclosamide may represent a promising strategy to enhance the efficacy of immune checkpoint blockade in solid tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1761715","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T06:37:45Z","timestamp":1773643065000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Identifying the therapeutic potential of niclosamide in overcoming IFN-gamma dependent cancer immune evasion in the tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Yue","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Carnegie Mellon University","place":["Pittsburgh, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Carnegie Mellon University","place":["Pittsburgh, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.01.002.IDO","article-title":"IDO in the tumor microenvironment: inflammation, counter-regulation and tolerance","volume":"37","author":"Munn","year":"2017","journal-title":"Trends Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/s41392-023-01332-8","article-title":"Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduction Targeting Ther"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1027124","article-title":"Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology","volume":"13","author":"Liu","year":"2022","journal-title":"Front Immunol Front Media S.A"},{"key":"B4","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.molcel.2020.10.015","article-title":"Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity","volume":"80","author":"Byun","year":"2020","journal-title":"Mol Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-020-18570-x","article-title":"PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade","volume":"11","author":"Peng","year":"2020","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","first-page":"14572","DOI":"10.1038\/ncomms14572","article-title":"Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice","volume":"8","author":"Lau","year":"2017","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1084\/jem.20160801","article-title":"PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity","volume":"214","author":"Juneja","year":"2017","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.cmet.2015.08.015","article-title":"MYC\/PGC-1\u03b1 balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells","volume":"22","author":"Sancho","year":"2015","journal-title":"Cell Metab"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-017-18762-4","article-title":"Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism","volume":"8","author":"Kim","year":"2018","journal-title":"Sci Rep Springer US;"},{"key":"B10","doi-asserted-by":"publisher","first-page":"15330338211036304","DOI":"10.1177\/15330338211036304","article-title":"Hypoxia and the tumor microenvironment","volume":"20","author":"Li","year":"2021","journal-title":"Technol Cancer Res Treat"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-018-1330-2","article-title":"The IFN-\u03b3\/PD-L1 axis between T cells and tumor microenvironment: Hints for glioma anti-PD-1\/PD-L1 therapy","volume":"15","author":"Qian","year":"2018","journal-title":"J Neuroinflammation. 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