ArticleClinical and molecular hepatology2026
COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2/HER3 signaling.
Article in Clinical and molecular hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- COLEC12high tumor-associated macrophages: A novel paracrine axis driving lenvatinib resistance in hepatocellular carcinoma: Editorial on "COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2/HER3 signaling".Clinical and molecular hepatology · 2026Article
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16 authors.
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Abstract
BACKGROUND/
aimsLenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood.
methodsIntegrated 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.
resultsResistant HCC exhibited significant enrichment of a COLEC12high 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.
conclusionsOur work establishes the COLEC12high 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.
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