ArticleCancer communications (London, England)2023
Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2-positive gastric cancer.
Article in Cancer communications (London, England), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 95 citations in OpenAlex.
- Metabolic immune checkpoints (MICs) in cancer: from molecular mechanisms to challenges and opportunities in clinical translation.Signal transduction and targeted therapy · 2026Review
- Glutamine metabolism in health and disease.Signal transduction and targeted therapy · 2026Review
- Molecular classification and precision therapy in gastric cancer: Current advances and future perspectives (Review).Oncology reports · 2026Review
- Beyond immunity: macrophage plasticity in vascular regeneration.npj biomedical innovations · 2026Review
- Impact of spatial distribution of M2 macrophages on prognosis and neoadjuvant chemotherapy resistance in gastric cancer.Journal of gastrointestinal oncology · 2026Article
- Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.Nature communications · 2026Article
- Review
- Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.Journal of nanobiotechnology · 2026Article
- The glycolysis-H4K12la-PKM2 positive feedback loop drives M2 polarization of macrophages in colorectal cancer.Clinical epigenetics · 2026Article
- Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.Nature communications · 2026Article
- Oxidative Stress Induced Senescent Macrophage-Driven Squamous Cell Carcinoma Invasion via Glutamine Metabolic Reprogramming.Aging cell · 2026Article
- Therapeutic potential of targeting macrophage polarization in metastatic gastric cancer: a review on core mechanisms and clinical progress.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Integrated Transcriptomics Reveals Evolutionary Trajectories and Cell Density-Dependent Mechanisms in Aldosterone-Producing Adenomas.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Ferroptosis and macrophage polarization: mechanisms, interplay, and implications for medical applications.Cell death discovery · 2026Review
- Multi-omics reveals CXCR4 drives immune escape in colorectal cancer via metabolic reprogramming and immune microenvironment remodeling.Cell death & disease · 2026Article
- Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.Genes & diseases · 2026Review
- SNHG12 drives gastric cancer progression by activating the Wnt/β-catenin-mediated serine synthesis pathway.Journal of translational medicine · 2026Article
- Targeting glutamine metabolism to modulate macrophage functions in the tumor microenvironment.Discover oncology · 2026Review
- Targeting the ODC1-YBX1 axis reverses gastric cancer chemoresistance via transcriptional control of SLC7A11-mediated ferroptosis.Cell death discovery · 2026Article
- Metabolic regulation of tumor-associated macrophage function and immunotherapy in cancer.Cancer biology & medicine · 2026Review
31 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTrastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.
methodsTrastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi-scale agent-based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.
resultsBased on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab-resistant HER2-positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tumor-derived GLS1 microvesicles drove M2 macrophage polarization. Furthermore, angiogenesis promoted trastuzumab resistance. IHC showed high glutamine metabolism, M2 macrophage polarization, and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nude mice. Mechanistically, the cell division cycle 42 (CDC42) promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B (NF-κB) p65 and drove GLS1 microvesicle secretion through IQ motif-containing GTPase-activating protein 1 (IQGAP1). Based on the ABM and in vivo experiments, we confirmed that the combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.
conclusionsThis study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism, M2 macrophage polarization, and pro-angiogenic function of macrophages, leading to acquired trastuzumab resistance in HER2-positive gastric cancer. A combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.
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