Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: Efficacy, Real-World Outcomes, and the Search for Predictive Biomarkers

Immunotherapy has significantly reshaped the management of malignant pleural mesothelioma (MPM), offering new therapeutic opportunities after decades in which platinum-pemetrexed chemotherapy represented the only systemic option. However, clinical benefit remains markedly heterogeneous, with outcomes strongly influenced by histologic subtype, patient characteristics, and real-world treatment conditions. Evidence from monotherapy trials has been inconsistent, whereas combination approaches-particularly nivolumab plus ipilimumab-have demonstrated improved survival compared with chemotherapy, mainly in non-epithelioid tumors. Nevertheless, real-world data consistently show lower efficacy and higher toxicity than registrational studies, especially among elderly and unselected populations. Recent translational work has highlighted the relevance of the tumor microenvironment and recurrent genomic alterations such as BAP1, NF2, and CDKN2A in shaping immune activity and potentially modulating response to immune checkpoint inhibitors. Transcriptomic signatures and circulating biomarkers-including soluble mesothelin-related peptide-have shown prognostic associations but no validated predictive value. Overall, current evidence suggests that sensitivity to immunotherapy in MPM arises from a complex interplay of genomic, immunologic, and clinical factors, and that no biomarker is yet suitable for guiding treatment decisions. Prospective studies integrating molecular and immune profiling will be essential to refine patient selection and advance toward a more rationally personalized use of immunotherapy.