Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8⁺ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8⁺ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8⁺ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8⁺ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

Chem Biol Drug Des. 2026 Sep;108(3):e70386. doi: 10.1111/cbdd.70386.

ABSTRACT

Emerging evidence indicates that coagulation-related molecular programs are associated with thrombosis, tumor progression, and molecular dysregulation in gastric cancer (GC). However, thrombosis-associated molecular features in GC and their potential links to inherited susceptibility remain insufficiently understood. Integrated analyses of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were performed to identify thrombosis-associated genes and establish a machine learning-based prognostic signature. Genome-wide association study (GWAS), expression quantitative trait loci (eQTL), transcriptome-wide association study (TWAS), and Mendelian randomization (MR) analyses were conducted to investigate susceptibility-associated transcriptional programs in GC. Functional assays were used to evaluate candidate genes associated with malignant phenotypes. Single-cell RNA sequencing (scRNA-seq) and cell-cell communication analyses were further performed to characterize cell-type-specific expression patterns and potential intercellular interactions. A total of 22 differentially expressed thrombosis-associated genes were identified, and a prognostic signature comprising 14 genes was established. The signature stratified patients into high- and low-risk groups and showed prognostic performance in both the training and validation cohorts. Integrative GWAS, eQTL, and TWAS analyses identified susceptibility-associated transcriptional programs that were positively correlated with the thrombosis-associated risk score. Silencing ACTN2 and CRYAB significantly reduced GC cell migration and invasion. scRNA-seq analysis revealed relatively high CRYAB expression in neutrophils, and CellChat analysis suggested potential neutrophil-B cell interactions involving COLLAGEN-related signaling. This integrative multi-omics study identified a thrombosis-associated molecular signature linked to prognosis and germline susceptibility-associated transcriptional programs in GC. ACTN2 and CRYAB may represent candidate genes associated with GC cell migration and invasion, while single-cell analysis suggested potential immune-related communication features.

PMID:42681916 | PMC:PMC13534880 | DOI:10.1111/cbdd.70386