Abstract Background: HER2-amplified metastatic colorectal cancer (CRC) represents an aggressive disease subtype with poor prognosis and limited response to standard therapies. The molecular mechanisms underlying its malignant behavior and immune evasion, particularly the contribution of specific genes and signaling pathways involved in tumor progression and immune regulation, remain insufficiently defined. This study investigated the biological mechanisms driving tumor progression and immune escape in HER2-amplified CRC. Methods: We analyzed GSDMB and HER2 expression, copy number variations (CNVs), and patient survival in The Cancer Genome Atlas (TCGA) cohort, and compared expression across clinical stages, BRAF mutation status, and microsatellite status. Mechanistic studies, including RT-qPCR, western blotting, flow cytometry, and immunofluorescence, were conducted to evaluate the effects of GSDMB overexpression on mitochondrial integrity, activation of the cGAS-STING pathway, and immune-related molecule expression. Transcriptome analyses were conducted to identify pathways enriched in GSDMB-high tumors. Results: GSDMB was the most significantly co-enriched gene in HER2-high CRC (FDR0.001). Although overall GSDMB expression was not associated with survival (p=0.55), high expression predicted poorer survival in stage IV patients (p=0.005). GSDMB and HER2 are adjacent on the chromosome, and HER2 amplification was consistently accompanied by GSDMB co-amplification; all patients with GSDMB CNV gains (6.4%) or losses (0.3%) showed corresponding HER2 CNV changes. GSDMB expression was significantly elevated in BRAF-mutant (p0.001) and MSI-H (p0.001) tumors. Transcriptomic analyses revealed that GSDMB overexpression was associated with enrichment of HER2 signaling and IFNα Response pathways (FDR0.001). Experimental validation demonstrated that GSDMB overexpression induced mitochondrial membrane pores, resulting in chronic, low-level leakage of mitochondrial double-stranded DNA into the cytoplasm, which activated the cGAS-STING pathway and induced chronic type I interferon responses. This, in turn, upregulated immune checkpoint molecules, impaired antigen presentation, and promoted T cell exhaustion/tolerance. Conclusion: GSDMB is a recurrently co-amplified gene in HER2-amplified CRC and remodels the tumor immune microenvironment via mitochondrial dysfunction and chronic cGAS-STING/type I interferon signaling, driving immune evasion. Although GSDMB alone is not prognostically significant across all stages, it elevated expression predicts poor outcomes in advanced metastatic disease. These findings highlight GSDMB and its downstream immune pathways as promising therapeutic targets and prognostic biomarkers in HER2-amplified CRC. Citation Format: Junyong Weng, Tianchen Xiong, Xinxiang Li, Ajay Goel. GSDMB drives cGAS-STING-mediated immune evasion in HER2-amplified colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 389.
Weng et al. (Fri,) studied this question.