Endometrial cancer (EC) of no specific molecular profile (NSMP) subtype lacks specific molecular features, and the relationship of tumor microenvironment (TME) and relapse in NSMP EC remains incompletely understood. This study integrates single-nucleus RNA sequencing, spatial transcriptomics, and multiplex immunohistochemistry to elucidate the TME and mechanisms of relapse in NSMP EC. The results showed reduced immune infiltration and increased immune-suppressive cells, including SPP1+ macrophages and regulatory T cells (Tregs) in NSMP EC. More epithelial cell clusters with high stemness scores are observed in primary NSMP EC tumors collected before recurrence. In NSMP EC, tip endothelial cells and MMP11+ LEF1+ cancer-associated fibroblasts (CAFs) are linked with angiogenesis and epithelial-mesenchymal transition, and CD4+ T cells remain in a stress-response state and are functionally impaired. Interestingly, a subset of tumor-associated macrophages (TAMs) characterized by SPP1 expression is discovered, which may remodel the tumor microenvironment by potentially promoting CD4+ T cells stress and maintaining epithelial cells stemness through SPP1-CD44, thereby potentially contributing to the proliferation and migration of tumor cells, which has verified by in vitro experiments. This study advances the mechanistic understanding of recurrence-related TME and provides a foundation for the development of personalized treatments for NSMP EC patients.