Multi-omics integration in malignant pleural mesothelioma: from molecular evolution and immune ecosystems to...

Malignant pleural mesothelioma (MPM) exhibits substantial molecular and cell-state heterogeneity, together with marked spatial variation in its immune and stromal microenvironment. Histological classification and individual biomarkers alone cannot adequately explain its evolution or heterogeneous treatment responses. This review critically integrates genomic, epigenomic, transcriptomic, single-cell, and spatial omics evidence along a conceptual continuum encompassing tumor-intrinsic molecular evolution, microenvironmental ecosystem remodeling, candidate stratification, and precision therapy. Current evidence indicates that alterations involving BAP1, CDKN2A/MTAP, and the NF2/Hippo pathway impose evolutionary constraints and create candidate therapeutic vulnerabilities but are insufficient to determine functional phenotypes independently. Epithelioid, uncommitted, and sarcomatoid malignant cell states may coexist within the same genetic clone, while immune and stromal features display pronounced regional heterogeneity. Based on published human MPM cohorts, we further propose four provisional immune-ecosystem archetypes: T-cell-inflamed, B-cell/tertiary lymphoid structure-organized, myeloid-dominant, and immune-desert. Tumor-intrinsic molecular states and stromal-spatial features are treated as interpretive modifiers. This literature-derived framework is intended for hypothesis generation and has not been developed or validated as a clinical classifier. At present, the principal value of multi-omics lies in mechanistic discovery and the design of biomarker-enriched clinical trials. Future studies should employ standardized assays in multicenter cohorts, independent external validation, formal archetype-by-treatment interaction testing within randomized trials, and longitudinal sampling to determine the treatment-predictive value and clinical feasibility of this framework.