Background: Colorectal cancer (CRC) is one of the most lethal malignancies worldwide with 850,000 deaths annually attributable to metastasis. Early-stage CRCs (stage I/II) are supposed to be curative by surgery. Nevertheless, up to 25% of these patients eventually succumb to metastasis. ¹Tumor microenvironment (TME) governs CRC progression and invasion, overall survival, and treatment response. ²Tumor-associated macrophages (TAMs), the most abundant immune population within TME, modulating tissue architecture and favor microenvironment for tumor cell by reducing T cells and NKs activities. ³Intratumor microbiome (IM) may promote cancer initiation and progression while interact closely with intestinal epithelial cells (IECs) and is crucial for innate and adaptive immune cells. Methods: We characterize TME through spatial whole transcriptomics (WT) approach in 150 early-stage CRC patients with clinically determined metastasis status using Nanostring GeoMx Digital Spatial Profiler, targeting interactions between TAMs (CD163 marker staining) and IM (RNAScope chromogenic assay) to identify pathogenic mechanisms in early-stage CRC metastasis, comparing the WT profiles stratified by region of interests (ROIs) with high bacteria commensal (Bac⁺) and low/no bacteria (Bac^-). Aim: We aim to elucidate the mechanisms underlying microbiome contributions to the TME and metastasis. Result: Pathway enrichment analysis identified 24 pathways up-regulated in Bac⁺ tumors compared to Bac^- tumors. Epigenetic modifications emerged as the potential mechanism leading to metastasis risk in Singapore early-stage CRC cohort. Histone deacetylase signaling pathway is upregulated three-fold in Bac⁺ ROIs in metastasis positive cases compared to metastasis negative cases. ⁴Microbiome-sensitive epigenetic mechanisms may alter epigenetic patterning in the host, influencing genetic predisposition and reshaping TME through activation/inactivation and immunosuppression of T and NK cells, contributing to metastasis risk in CRC patients.