Abstract

Pseudomyxoma peritonei (PMP) is characterized by progressive mucus accumulation, extensive stromal fibrosis, rare extraperitoneal metastasis, limited therapeutic options, and frequent recurrence. However, the microenvironmental ecosystem of PMP, particularly in metastatic lesions, remains poorly understood. Here, we integrated single‐cell RNA sequencing, whole‐exome sequencing, bulk RNA sequencing, and histopathologic validation to construct a high‐resolution atlas of primary and paired metastatic tumors. Epithelial cells showed distinct functional states, including a TFF3 + mucus secretion‐associated state and a MACC1 + malignant‐associated state. Metastatic lesions showed coordinated microenvironmental reprogramming, including POSTN + fibrosis‐associated fibroblasts, CXCL5 + macrophages linked to local immunosuppressive signaling, and immune exclusion associated with a collagen‐rich stromal barrier. We also observed extensive lipid metabolic activity and identified a candidate pro‐angiogenic network involving POSTN + fibroblasts, RSPO3 + pericytes, and endothelial cells, potentially mediated by VEGFA–VEGFR2 signaling. Retrospective observations from three recurrent PMP cases further suggested the potential therapeutic value of VEGFR2‐targeted anti‐angiogenic therapy. Overall, this study provides a comprehensive single‐cell transcriptomic atlas of PMP and a resource for developing novel and combination therapeutic strategies. This study presents a single‐cell atlas of pseudomyxoma peritonei spanning primary and paired metastatic lesions. Distinct epithelial substates, stromal remodeling, immune exclusion, lipid metabolic reprogramming, and a candidate angiogenic network were identified in metastatic lesions. These findings advance the understanding of PMP biology and provide a resource for the development of novel targeted and combination treatment strategies.