Photo-triggered engineered microbes achieving dual epigenetic immunomodulation for gastric cancer

DNA methylation serves as an essential epigenetic mechanism for the regulation of gene expression. One of the earliest and most common changes seen in cancer is abnormal DNA methylation at CpG sites, which may encourage tumor development by silencing tumor suppressor gene transcription. The DNMT1 inhibitor AZA can delay cancer progression by inhibiting DNA methylation and enhancing tumor immunogenicity, yet its clinical efficacy in gastric cancer is limited by poor specificity, instability, and low retention. To address this, we developed a light-triggered engineered microbe, AM@Ec, utilizing Escherichia coli (MG1655) as a carrier that selectively targets the tumor microenvironment (TME). This system delivers Mo_1.33C-AZA to the tumor core, enhancing anti-tumor efficacy through DNA methylation inhibition. Additionally, iMXene (Mo_1.33C) demonstrates outstanding CT imaging and photothermal properties, making it suitable for photothermal therapy (PTT), and synergize with epigenetic regulation to enhance apoptosis in gastric cancer cells. This approach also triggers immunogenic cell death, promotes dendritic cell maturation, reshapes the TME, and activates systemic immunity, generating immune memory to prevent metastasis. Furthermore, epigenomic and transcriptomic analyses confirmed that the combined treatment not only significantly reduced methylation levels within tumor tissues but also effectively activated immune cell-related transcriptional pathways to promote anti-tumor immune responses. In summary, this study introduces an innovative diagnostic and therapeutic 808 nm NIR laser irradiation-triggered engineered microbe that establishes an efficient delivery platform for DNMT1 inhibitors and iMXene, activating epigenetic immunity and paving the way for the broad application of epigenetic regulation in solid tumor treatment.