In this study, we not only furtherly revealed that POSTN+ myofibroblast cells and APOC1+APOE+ macrophages are major components of the ESCC metastatic microenvironment but also for the first time propose two models of potential intercellular interactions in the context of ESCC tumor ecosystem: one is tumor cells‐led supporting tumor growth in primary tumor and the other is APOC1+APOE+ macrophages‐mediated supporting cell adhesion and distant metastasis in lymph nodes. This evidence concerns the gene APOE and neoplasm.