Molecular biology and treatment of peritoneal metastatic disease

Peritoneal metastatic disease (PMD) is a frequent and aggressive manifestation of abdominal cancers with limited treatment options and poor outcomes. This thesis investigates the biological mechanisms driving peritoneal dissemination by examining the interplay between tumor-intrinsic characteristics and the peritoneal microenvironment. Through transcriptomic analyses, single-cell profiling, and translational models, we demonstrate that colorectal cancer-associated PMD is strongly enriched for the mesenchymal CMS4 subtype and identify key drivers of metastatic progression. We reveal that the peritoneal immune niche, dominated by immunosuppressive resident macrophages, actively promotes tumor growth and immune evasion. Furthermore, humanized immune system models provide insight into tumor–immune interactions and therapeutic responses. Finally, we identify mitochondrial metabolism as a targetable vulnerability in PMD and demonstrate the therapeutic potential of mitochondrial-disrupting compounds. Together, these findings establish a framework for biology-driven, subtype-guided therapeutic strategies to improve treatment of PMD.