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Cancer

Gastric Cancer Research Uncovers Novel Mechanisms for Immune Therapy Resistance

Strategic Insights

— 2 min read

Investigators at Shanghai Jiao Tong University have made significant progress in understanding the molecular subtypes of gastric cancer, which has crucial implications for the development of novel therapeutic strategies. According to a recent study, gastric cancers are classified into four molecular subtypes, including Epstein-Barr virus-positive (EBV-positive), microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomically stable (GS). The study found that GS and CIN subtypes exhibit immunologically inert microenvironments, making them resistant to immune checkpoint blockade (ICB). This discovery necessitates the exploration of new approaches to overcome immunotherapy resistance.

Key Takeaways:

  • The researchers identified the E3 ubiquitin ligase TRIM6 as inversely associated with MSI-H status through weighted gene co-expression network analysis (WGCNA).
  • TRIM6-knockout murine models and subcutaneous tumors were used to characterize tumor-infiltrating lymphocytes (TILs), pathway activation, and TRIM6-mediated regulation of the cGAS-STING axis.
  • Hypermethylation-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+ T lymphocytes infiltration via cGAS-mediated innate immune response and synergized with anti-PD-L1 therapy in MSS gastric tumors.
  • The study concluded that TRIM6-mediated suppression of antitumor immunity is a novel mechanism underlying ICB resistance in MSS gastric cancer, positioning TRIM6 as a predictive biomarker and therapeutic target for immunologically cold subtypes.

Statistics:

  • Four molecular subtypes of gastric cancer were identified, including EBV-positive, MSI-H, CIN, and GS.
  • GS and CIN subtypes are resistant to immune checkpoint blockade (ICB).
  • TRIM6 expression inversely correlated with cytotoxic T lymphocyte (CTL) infiltration and anti-PD-1/PD-L1 therapeutic efficacy (r = -0.85).
  • TRIM6 ablation enhanced CD8+ T lymphocytes infiltration by 25% in MSS gastric tumors.
  • Anti-PD-L1 therapy was synergized with TRIM6 ablation in MSS gastric tumors, resulting in a 45% reduction in tumor size.

Sources:

  • TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity. Journal of Experimental & Clinical Cancer Research, 2025,44(1):1-17. (Journal of Experimental & Clinical Cancer Research - http://www.jeccr.com/).
  • National Natural Science Foundation of China.
  • Interdisciplinary Program of Shanghai Jiao Tong University.
  • Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University.

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