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However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood.Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous\/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort.Results: Resistant HCC exhibited significant enrichment of a COLEC12&lt;sup&gt;high&lt;\/sup&gt; TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2\/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2\/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models.Conclusions: Our work establishes the COLEC12&lt;sup&gt;high&lt;\/sup&gt; TAM\/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.<\/jats:p>","DOI":"10.3350\/cmh.2025.1059","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T05:34:13Z","timestamp":1768887253000},"page":"772-786","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2\/HER3 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