{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:50:37Z","timestamp":1781661037483,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"46","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Immune checkpoint inhibitors (ICIs) combined with anti\u2010angiogenic agents manifest improved survival in advanced hepatocellular carcinoma (HCC), but responses remain heterogeneous. Although high PIVKA\u2010II expression correlates with advanced disease stage, early recurrence, shorter survival, and may predict resistance to anti\u2010PD\u20101 plus lenvatinib therapy, the tumor microenvironment (TME) and resistance mechanisms in HCC with high PIVKA\u2010II expression remain unclear. Clinical data from 156 resected HCC patients and 104 patients treated with anti\u2010PD\u20101 plus lenvatinib are analyzed to correlate PIVKA\u2010II expression with clinical features and outcomes. Single\u2010cell RNA sequencing (scRNA\u2010seq) is performed on tumors from 15 untreated and 7 treated patients. Mechanistic findings are validated in vitro and in vivo. High PIVKA\u2010II expression is associated with advanced disease stage, increased microvascular invasion (MVI), early recurrence, and poor response to therapy. ScRNA\u2010seq revealed an immunosuppressive TME enriched with regulatory T cells (Tregs), exhausted CD8\u207a T cells, and SPP1\u207a tumor\u2010associated macrophages (TAMs). Mechanistically, tumors with high PIVKA\u2010II expression upregulated NQO1, which stabilized p65 by inhibiting ubiquitination, activating the NF\u2010\u03baB\/CXCL12 axis, and recruiting Tregs. This pathway mediated therapeutic resistance. Plerixafor, a CXCL12 inhibitor, disrupted this axis and significantly enhanced anti\u2010tumor efficacy when combined with anti\u2010PD\u20101 plus lenvatinib in vivo. PIVKA\u2010II is a potentially effective biomarker for predicting resistance to anti\u2010PD\u20101 plus lenvatinib therapy. Its high expression denotes an immunosuppressive TME. Targeting the NQO1\/CXCL12\/Tregs\u00a0axis with Plerixafor may restore sensitivity and improve outcomes.<\/jats:p>","DOI":"10.1002\/advs.202511152","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T03:47:22Z","timestamp":1759290442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["NQO1\/p65\/CXCL12 Axis\u2010Recruited Tregs Mediate Resistance to Anti\u2010PD\u20101 Plus Lenvatinib Therapy in PIVKA\u2010II\u2010Positive Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Biao","family":"Gao","sequence":"first","affiliation":[{"name":"Faculty of Hepato\u2010Pancreato\u2010Biliary Surgery Chinese PLA General Hospital  Beijing 100853 China"},{"name":"Institute of Hepatobiliary Surgery of Chinese PLA  Beijing 100853 China"},{"name":"Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA  Beijing 100853 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