Lack of resolution of inflammation marks malignant pleural mesothelioma progression.

Aim: Malignant pleural mesothelioma (MPM) is a paradigmatic inflammation-associated cancer and a major therapeutic challenge due to its resistance to treatment. Inflammation is thought to promote both tumor progression and therapy resistance. Senescence-associated secretory phenotype (SASP)-mediated, chemotherapy-induced release of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) contributes to pemetrexed resistance in MPM cells in vitro. Methods: Pro-inflammatory mediators (PIMs) and specialized pro-resolving mediators (SPMs) were quantified in pleural exudates using liquid chromatography-tandem mass spectrometry. Single-cell RNA-sequencing datasets were analyzed to assess the distribution of SPM-producing enzymes between mesothelial and mesothelioma cells in both tumor tissue and uninvolved pleura. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used to derive a composite prognostic score (CPS) from SPM-related gene expression. Results: Chemotherapy-treated patients exhibited a reduction in SPMs - including resolvins, protectins, and maresins - alongside increased prostaglandin levels. Single-cell analysis revealed differential partitioning of SPM-producing enzymes, with lower expression in mesothelioma cells compared with mesothelial cells. A five-gene CPS derived from this lipid mediator landscape independently predicted overall survival beyond conventional clinical parameters. Conclusion: Chemotherapy alters the lipid mediator composition of pleural exudates in MPM by reducing SPMs, thereby disrupting resolution pathways. This effect is consistent with an intrinsic imbalance in expression between mesothelial and mesothelioma cells. Together, these findings suggest that impaired resolution of inflammation contributes to a pro-tumorigenic, pro-inflammatory, and chemoresistant microenvironment in MPM, with potential prognostic implications.