ArticleJournal of experimental & clinical cancer research : CR2025
TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Molecular classification and precision therapy in gastric cancer: Current advances and future perspectives (Review).Oncology reports · 2026Review
- cGAS-STING pathway activation drives the cold-to-hot tumor transition and sensitizes immunotherapy.Cancer biology & medicine · 2026Review
- Gastric Cancer Organoids: Mechanistic Insights, Drug Discovery, and Translational Advances in Precision Medicine.Journal of gastric cancer · 2026Review
- Pan-cancer 8q24 amplification predicts primary immunotherapy resistance and therapeutic vulnerabilities.iScience · 2026Article
- Olverembatinib, a novel BCR-ABL tyrosine kinase inhibitor, exhibits anti-tumor activity and synergizes with gemcitabine in pancreatic ductal adenocarcinoma.NPJ precision oncology · 2026Article
- Targeting the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway: An Emerging Therapeutic Strategy for Digestive Diseases.Clinical and translational gastroenterology · 2026Review
- The cGAS-STING pathway in tumor immunity: dual roles, regulatory mechanisms, and precision therapeutic strategies.Frontiers in pharmacology · 2026Review
- Decoding the PTM code of cGAS-STING in gastric cancer: from innate DNA sensing to precision combination therapy.Frontiers in immunology · 2026Review
- The chromosomal instability associated gene C2orf76 exerts dual roles in colorectal cancer through pyroptosis and chemotherapy response.Frontiers in oncology · 2026Article
- TRIM family proteins: dual roles in tumor immunity.Frontiers in cell and developmental biology · 2026Review
- Immunotherapy rechallenge in gastric cancer: resistance mechanisms, molecular stratification, and precision decision-making.Frontiers in immunology · 2026Review
- In Situ Vaccination by Tumor Ablation: Principles and Prospects for Systemic Antitumor Immunity.Vaccines · 2025Review
- Potential of Adora2b as an immunotherapeutic target for gastric cancer.Frontiers in immunology · 2025Review
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Authors and funding
8 authors.
Funding
Abstract
backgroundGastric cancers are classified into four molecular subtypes according to The Cancer Genome Atlas (TCGA) classification: Epstein-Barr virus-positive (EBV-positive), microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomically stable (GS). Unlike MSI-H gastric cancer, GS and CIN subtypes exhibit immunologically inert microenvironments and demonstrate minimal response to immune checkpoint blockade (ICB), necessitating novel strategies to overcome immunotherapy resistance.
methodsThrough weighted gene co-expression network analysis (WGCNA), we identified the E3 ubiquitin ligase TRIM6 as inversely associated with MSI-H status. TRIM6-knockout murine models and subcutaneous tumors were subjected to flow cytometry, RNA sequencing, immunoblotting, and ubiquitination assays to characterize tumor-infiltrating lymphocytes (TILs), pathway activation, and TRIM6-mediated regulation of the cGAS-STING axis.
resultsHypermethylation-mediated TRIM6 downregulation distinguished MSI-H from microsatellite stable (MSS) gastric cancers. Clinically, TRIM6 expression inversely correlated with cytotoxic T lymphocyte (CTL) infiltration and anti-PD-1/PD-L1 therapeutic efficacy. Mechanistically, TRIM6 catalyzed K27-linked polyubiquitination of cGAS, triggering its proteasomal degradation and consequent suppression of the cGAS-STING pathway. TRIM6 ablation enhanced CD8
conclusionsOur results elucidate TRIM6-mediated suppression of antitumor immunity as a novel mechanism underlying ICB resistance in MSS gastric cancer, positioning TRIM6 as both a predictive biomarker and therapeutic target for immunologically cold subtypes.
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