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Background Diffuse pleural mesothelioma (DPM) is an aggressive malignancy with poor outcomes even in potentially resectable disease. With an evolving understanding of the role of pleurectomy/decortication (P/D) in patients with resectable disease, the need to optimize and improve upfront therapies is more urgent. Here, we report on transcriptional and spatial correlates of progression free survival from this single institution prospective pilot study of nivolumab with platinum (cisplatin/carboplatin) and pemetrexed prior to P/D (2 cycles) for patients with resectable DPM ( NCT04162015).Methods To comprehensively assess tumor and immune microenvironment changes after immunotherapy with chemotherapy in DPM, single cell RNAseq was performed on 20 resection specimens from 16 patients with available material, including three patients with matched pre/post resection specimens. In addition, peripheral blood mononuclear cell (PBMC) from pre/post treatment, whole exome sequencing, and spatial analyses were studied to comprehensively understand treatment resistance to immunotherapy with chemotherapy in this rare tumor type. Here we report on the transcriptional and spatial tumor microenvironment changes that correlate with response after treatment from generating the largest cohort of DPM resection specimens analyzed by single-cell RNAseq.Results 22 patients received neoadjuvant chemo-immunotherapy and 19 underwent attempted P/D (2 progressed and 1 declined surgery) within 30 days of the planned resection date. Of the 19 patients that went for P/D, the median OS from the start of neoadjuvant therapy was 34mos with a progression free survival (PFS) of 14mos (median follow-up: 32mos). We discover that after two cycles of chemotherapy with nivolumab long-term responders (PFS>12 months) have a tumor microenvironment enriched by lymphocytes (CD4+ and CD8+ T cells as well as NK cells) while short-term responders had an abundance of myeloid cells. Short term responders had a clear enrichment of an IFN-responsive signature in tumor cells. Further analysis revealed that enrichment of clonally expanded CD8+ tumor reactive T-cells with exhaustion features, GZMK+ effector memory CD8+ T cells, and a shift from monocytes to APOE+ macrophages were features of the tumor immune compartment in long term responders. Moreover, we discover that DPM cells exist on a phenotypic-continuum between mesothelial-like and fibroblast-like states. Leveraging spatial transcriptomics, we find fibroblast-like tumor cells occupy spatially distinct tumor regions characterized by poor immune infiltrate and high TGFβ-signatures.Conclusions This in-depth characterization of the largest cohort of DPM resection specimens analyzed at a single cell level after neoadjuvant treatment provides foundational insights to characterize DPM responders to chemo-IO and support future therapeutic development.