<p>Malignant pleural mesothelioma (MPM) is a highly aggressive and molecularly heterogeneous malignancy with poor prognosis. Here, we performed an integrative multi-omic analysis combining bulk transcriptomics, copy number variation profiling, and single-cell RNA sequencing to systematically characterize MPM heterogeneity. Using non-negative matrix factorization, we identified three robust molecular subtypes (S-I, S-II, and S-III) with distinct transcriptional programs, genomic alterations, and tumor microenvironment compositions. Subtype S-I exhibited immune-inflamed signatures with abundant cytotoxic T cells and activated dendritic cells, suggesting potential responsiveness to immunotherapy. S-II was characterized by metabolic reprogramming and mTORC1 pathway activation, whereas S-III displayed stromal enrichment, extracellular matrix remodeling, and suppressed apoptotic signaling. Single-cell analysis revealed subtype-specific distributions of malignant and stromal cell subsets, corroborating bulk-level observations and highlighting intratumoral heterogeneity. Collectively, these findings refine the molecular classification of MPM, uncover subtype-specific regulatory programs, and identify potential therapeutic vulnerabilities, providing a framework for precision medicine strategies in this challenging malignancy.</p>