{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:18:19Z","timestamp":1787894299014,"version":"build-2784847793"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lenvatinib is a first-line multi-target tyrosine kinase inhibitor for hepatocellular carcinoma (HCC) that exerts anti-angiogenic effects by blocking VEGF signaling. However, its clinical efficacy is often compromised by adaptive resistance. Nifuroxazide, an anti-diarrheal agent, has been identified by our group as a potent inhibitor of PD-L1 expression in HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to evaluate the therapeutic potential and underlying molecular mechanisms of nifuroxazide combined with lenvatinib against HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      , HCC cell proliferation, colony formation, and migration were assessed, and Western blot was used to detect p-STAT3, STAT3, PD-L1, and VEGF levels.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , antitumor efficacy was evaluated in mouse xenograft models. Tumor tissues were analyzed by immunohistochemistry, TUNEL, and H&amp;amp;E staining, while flow cytometry was used to measure CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell proportions in the tumor microenvironment, peripheral blood, and spleen.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The combination synergistically inhibited HCC cell proliferation and migration, and downregulated PD-L1, p-STAT3, and VEGF expression. It also markedly suppressed tumor growth, induced apoptosis, and enhanced CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell infiltration and distribution.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Nifuroxazide potentiates lenvatinib-induced antitumor activity by regulating the STAT3\/PD-L1 axis and enhancing antitumor immune responses. This combination provides a promising therapeutic strategy for HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1937787","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:33:13Z","timestamp":1787891593000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination therapy with Nifuroxazide and Lenvatinib exerts superior anti-hepatocellular carcinoma effect by enhancing the anti-tumor immune response"],"prefix":"10.3389","volume":"16","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Technology, Shangqiu Medical College","place":["Shangqiu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Geng","sequence":"additional","affiliation":[{"name":"Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 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Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan Medical University","place":["Xinxiang, China"]},{"name":"Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Xinxiang Central Hospital","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xinxiang Key Laboratory for Tumor Radiotherapy and Targeted Therapy, the Third Affiliated Hospital of Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiesuo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal 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