Personalized chemotherapy guidance using patient-derived scaffolds from peritoneal colorectal metastases.

Peritoneal metastases from colorectal cancer are associated with poor survival and limited therapeutic efficacy. To model patient-specific treatment responses, we generated patient-derived scaffolds (PDS) through tumor decellularization, preserving critical microenvironmental features for functional ex vivo analysis. PDS from 75 metastases were recellularized with HT29 cells and treated with 5-fluorouracil (5-FU), mitomycin C, or oxaliplatin. Gene expression related to proliferation, epithelial phenotype, epithelial-mesenchymal transition, and stemness was quantified and integrated into a composite treatment score to estimate the most favorable therapy for each patient. Treatment responses were influenced by both drug exposure and the patient-specific microenvironment. Importantly, subcluster distributions differed across treatment arms, supporting the concept that therapeutic response is modulated by microenvironmental context rather than being solely drug dependent. These findings were supported in a smaller validation cohort using HCT116 and DLD-1 cells recellularized into selected PDS. Treatment scoring based on HT29 cells revealed heterogeneous sensitivity patterns, with 38.7% of PDS responding best to 5-FU, 36% to mitomycin C, and 25.3% to oxaliplatin. Patients with more than two favorable treatment scores had improved disease-free survival (p = 0.0415). The PDS platform enables functional profiling of chemotherapy-response and may support individualized treatment strategies for colorectal cancer patients with peritoneal metastases.