Patient-Derived Organoid Models and Precision HIPEC in Diffuse Malignant Peritoneal Mesothelioma: Modeling Heterogeneity to Address Recurrence.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy for which cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is central to treatment in appropriately selected patients. Recurrence remains common even after complete macroscopic cytoreduction. Current HIPEC regimens are protocolized at the institutional and population levels but are not individualized using site-specific molecular or functional tumor biology. We performed a narrative review of clinical, genomic, epigenetic, immune, microenvironmental, and patient-derived organoid evidence relevant to DMPM, CRS/HIPEC, and treatment resistance. Recurrence is multifactorial, with plausible contributions from spatial, histologic, genomic, epigenetic, immune, stromal, and pharmacokinetic heterogeneity. Three primary reports provide direct DMPM organoid evidence, including preliminary demonstrations of patient-specific drug response and discordant responses among anatomically distinct implants. However, these platforms differ biologically, and predictive thresholds, analytical reproducibility, turnaround time, and microenvironmental modeling remain unvalidated. Multi-site organoid pharmacotyping integrated with molecular profiling is therefore a plausible strategy for studying HIPEC resistance. Translation requires a staged pathway encompassing analytical validity, blinded clinical validity, and clinical-utility testing. Precision HIPEC should presently be considered an investigational, validation-ready framework rather than a standard of care.