TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity

Abstract Background Gastric 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. Methods Through 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. Results 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. Conclusions Our 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.