Clinical and Molecular Hepatology | COLEC12high Tumor-Associated Macrophages Mediate Lenvatinib Resistance in Hepatocellular Carcinoma via the NRG1-HER2/HER3 Signaling Axis

This study reveals a novel mechanism by which a specific macrophage subset in the tumor microenvironment drives lenvatinib resistance through NRG1, providing an actionable intervention strategy to overcome resistance to targeted therapies, with direct implications for designing combination treatments in hepatocellular carcinoma.

 

Literature Overview

The article titled 'COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2/HER3 signaling,' published in the journal Clinical and Molecular Hepatology, systematically investigates the critical role of tumor-associated macrophages in drug resistance in hepatocellular carcinoma. By integrating patient samples with mouse models, the study identifies a macrophage subset highly expressing COLEC12, revealing that it induces cancer stemness and drug resistance by secreting NRG1 to activate the HER2/HER3 signaling pathway in tumor cells. This finding provides new insights into overcoming resistance by targeting the tumor microenvironment.

Background Knowledge

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Lenvatinib, a first-line multi-kinase inhibitor in systemic therapy, shows initial efficacy but rapidly leads to resistance, posing a major clinical challenge. The role of the tumor microenvironment (TME) in resistance is increasingly recognized, yet the heterogeneity of tumor-associated macrophages (TAMs) and their pro-resistance functions remain incompletely understood. Although previous studies suggest TAMs can mediate sorafenib resistance via pathways such as HGF/MET or CXCR2, the specific TAM subsets and mechanisms involved in lenvatinib resistance remain unclear. Moreover, while NRG1, a ligand for HER2/HER3, has been established as a driver in cancers like lung cancer, its functional role and cellular source in HCC remain controversial. This study addresses this knowledge gap by using single-cell transcriptomics and functional screening to focus on the COLEC12^high TAM subset, systematically elucidating its role and mechanism in lenvatinib resistance, thereby filling a critical void in the field.

 

 

Research Methods and Experiments

The study employed a multidimensional experimental system to validate the function of COLEC12^high TAMs. First, by integrating transcriptomic data from HCC patient tissues and mouse resistance models with CIBERSORT analysis, the researchers found significant enrichment of TAMs in resistant tumors and identified a conserved 58-gene resistance-associated macrophage signature. Using CRISPR-SAM activation screening, they demonstrated that COLEC12 overexpression significantly enhances hepatoma cell survival under lenvatinib treatment. In vitro experiments using THP-1-derived macrophages, patient-derived monocyte-derived macrophages (MDMs), and primary TAMs, along with conditioned medium (CM) assays, confirmed that factors secreted by COLEC12^high macrophages promote tumor cell proliferation, colony formation, and reduce drug sensitivity. In vivo, subcutaneous and orthotopic transplantation models verified that COLEC12^OE CM accelerates tumor growth and diminishes lenvatinib efficacy. Furthermore, through ChIP-qPCR, Co-IP, and molecular docking experiments, the study elucidated that COLEC12 binds to STAT1 via its intracellular domain, inhibiting its phosphorylation, thereby relieving suppression of STAT3 and promoting NRG1 transcription. Clinical cohort analysis showed that NRG1 expression was significantly associated with treatment response and survival. Finally, patient-derived organoids (PDOs) and patient-derived xenograft (PDXs) models demonstrated that the bispecific antibody zenocutuzumab could restore sensitivity to lenvatinib.

Key Conclusions and Perspectives

• In HCC resistant to lenvatinib, COLEC12^high TAMs are significantly enriched and associated with poor prognosis; this finding suggests COLEC12 as a potential prognostic biomarker to guide clinical monitoring strategies
• COLEC12^high TAMs drive cancer stemness and resistance by paracrine secretion of NRG1, activating HER2/HER3–AKT signaling in tumor cells; this provides a mechanistic rationale for targeting the NRG1–HER2/HER3 axis and supports the development of combination therapies
• COLEC12 promotes NRG1 transcription by binding and inhibiting STAT1 phosphorylation, thereby relieving its suppression of STAT3; this non-canonical signaling pathway reveals a novel role for COLEC12 in macrophage functional reprogramming, expanding our understanding of TAM polarization regulation
• High NRG1 expression predicts poor response to lenvatinib and shorter survival, while zenocutuzumab can restore drug sensitivity; this indicates NRG1 is a druggable therapeutic vulnerability, providing a clear biomarker-driven strategy for drug development

Research Significance and Prospects

This study reveals a novel mechanism of lenvatinib resistance from the perspective of the tumor microenvironment, highlighting the critical role of TAM subset heterogeneity in the failure of targeted therapies. The identified COLEC12–NRG1–HER2/HER3 axis not only provides new biomarkers for resistance prediction but also proposes clinically translatable intervention strategies. Notably, the efficacy of zenocutuzumab in PDO and PDX models strongly supports clinical trials evaluating its combination with lenvatinib. Moreover, this mechanism is independent of tumor cell-autonomous resistance, suggesting that combining microenvironment-targeted and tumor cell-targeted therapies may more effectively overcome adaptive resistance.

 

 

Conclusion

This study systematically elucidates the molecular mechanism by which COLEC12^high tumor-associated macrophages drive hepatocellular carcinoma stemness and lenvatinib resistance through NRG1-mediated activation of the HER2/HER3 signaling pathway. This discovery not only highlights the dominant role of the tumor microenvironment in targeted therapy resistance but also identifies NRG1 as a key druggable target. From bench to bedside, this research provides new prognostic biomarkers (COLEC12, NRG1) and therapeutic strategies (combination of zenocutuzumab and lenvatinib) for HCC patients, potentially improving the limitations of current first-line treatments. Especially in the context of precision medicine, selecting patients with high NRG1 expression for combination therapy may significantly enhance treatment efficacy, marking a crucial step toward personalized, microenvironment-targeted therapy. This work lays a solid foundation for comprehensive treatment strategies in HCC and holds significant translational value.

 

Jianxing Zhang, Liang Qiao, Zongfeng Wu, Yi Niu, and Binkui Li. COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2/HER3 signaling. Clinical and Molecular Hepatology.