Metastasis predicts poor prognosis in patients with esophageal squamous cell carcinoma, whereas the regulatory mechanism of metastasis remains largely unknown. In this study, by using murine tumor metastasis model and spatial transcriptome analysis, we aimed to decipher the molecular basis of metastasis. Implantation of NRS1M squamous cell carcinoma cells into C3H/HeN mice gave rise to the growth of primary tumor, and elicited lymph node and lung metastasis. We isolated enhanced metastatic cells (em-NRS1M cells) by in vivo passage. RNA-Seq analysis revealed that cytokines network was perturbed in em-NRS1M cells compared with parental cells, implicating intrinsic immunomodulation in em-NRS1M cells. Immunohistochemical staining demonstrated that in vivo NRS1M tumors exhibited focal immunosuppressive areas featured by decreased CD8-positive T cells and CD11c-positive dendritic cells. We performed spatial transcriptome analysis (Visium) with tissue sections of em-NRS1M tumors and identified the tumor areas with gene signatures of immunosuppression, in which antigen presentation and interferon response were downregulated. Importantly, metastasis-related genes were significantly upregulated in the areas. Furthermore, we identified Galectin-X as a novel metastasis-driving factor. Our data suggest that immunosuppression-associated Galectin-X plays a crucial role in tumor metastasis and may be a potential target of cancer immunotherapy.