bims-mesote 2026-06-14 papers

Issue of 2026–06–14
four papers selected by
Laura Mannarino, Humanitas Research

Curr Oncol Rep. 2026 Jun 08. pii: 65. [Epub ahead of print]28(1):

The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves.

Mehmet Kucukoner, Tarik Demir, Abduljalil Mohammed Alsubaie, Ulas Alabalik, Aisha K Ibrahim, Mariaelena Pierobon, Lance Liotta.

PURPOSE OF REVIEW: Malignant pleural mesothelioma (MPM) remains a rare but highly aggressive malignancy with limited treatment options and poor prognosis. For nearly twenty years, platinum-pemetrexed chemotherapy has persisted as the unchanged standard treatment; although recent progress in immunotherapy has modestly disrupted this therapeutic plateau, survival outcomes remain disappointingly limited. This review aims to provide a comprehensive overview of the epigenetic landscape of MPM, focusing particularly on the oncogenic and therapeutic implications of enhancer of zeste homolog 2 (EZH2), and to discuss its potential as a target for novel therapeutic strategies and combination regimens.
RECENT FINDINGS: Epigenetic dysregulation has emerged as a central driver of mesothelioma pathogenesis. EZH2, the catalytic component of the polycomb repressive complex 2 (PRC2), mediates histone H3K27 trimethylation, silencing tumor suppressor genes and promoting malignant transformation. In addition to its canonical role, EZH2 has non-canonical oncogenic effects that modulate transcription, apoptosis, DNA repair, and immune evasion. High EZH2 expression correlates with BAP1 loss, which enhances chromatin remodeling defects and disease aggressiveness. Preclinical and early clinical data demonstrate that EZH2 inhibitors-including tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, and novel PROTAC-based degraders such as MS1943-can suppress tumor progression, modulate the tumor immune microenvironment, and restore therapeutic sensitivity. Furthermore, combination approaches integrating EZH2 inhibition with chemotherapy or immune checkpoint blockade show synergistic potential in overcoming resistance. EZH2 represents a pivotal epigenetic regulator and a promising therapeutic target in MPM. Further understanding the dual canonical and non-canonical roles of EZH2 in tumor biology will be key to optimizing targeted and combinatorial treatment strategies. Future research should focus on translating EZH2 inhibition into clinical benefit, identifying predictive biomarkers of response, and exploring rational combinations with chemotherapy, targeted drugs, or immunotherapy to improve survival outcomes in mesothelioma patients.

Keywords: BAP1; EZH2; Epigenetics; Immunotherapy; Mesothelioma; PRC2

DOI: https://doi.org/10.1007/s11912-026-01754-x

Front Immunol. 2026 ;17 1782708

Tumor treating fields in malignant pleural mesothelioma: from cytoskeletal collapse to immunophenotypic conversion.

Xiaofeng Ma, Zhuo Zuo, Yulong Sun, Hong An.

The therapeutic efficacy in malignant pleural mesothelioma (MPM) is severely hindered by its dense stromal barrier and immunosuppressive microenvironment. Although Tumor Treating Fields (TTFields) have demonstrated significant survival benefits in clinical trials, their underlying mechanisms extend well beyond simple mitotic arrest. This review delineates a "multidimensional biophysical remodeling" atlas of TTFields in MPM. First, we highlight that TTFields physically disrupt actin-dependent intercellular "tunneling nanotubes, " thereby severing the tumor's communication and metabolic rescue networks. Second, physical stress downregulates the Fanconi Anemia-BRCA pathway, inducing a state of "conditional BRCAness" that specifically sensitizes tumors to DNA-damaging agents. Finally, this cascade triggers immunogenic cell death and orchestrates a chemokine storm, which is hypothesized to facilitate the conversion of the tumor microenvironment from an immune "cold" to a "hot" phenotype. Collectively, by integrating the physical disintegration of subcellular structures with immunological remodeling, TTFields may offer a hypothetical theoretical framework for overcoming therapeutic resistance in MPM.

Keywords: immunogenic cell death; malignant pleural mesothelioma; physio-immunological remodeling; tumor microenvironment; tumor treating fields

DOI: https://doi.org/10.3389/fimmu.2026.1782708

Semin Nucl Med. 2026 Jun 10. pii: S0001-2998(26)00121-2. [Epub ahead of print]

The diagnostic performance and clinical value of [18F]FDG PET/CT in pleural mesothelioma - A systematic review and meta-analysis.

Anne H Thostrup, Natasja U Stubbe, Mathias P Schreiner, Morten Bentestuen, Anne V Olesen, Helle D Zacho.

PURPOSE: This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of FDG PET/CT for diagnosing pleural mesothelioma in treatment-naïve patients using histopathology as reference standard. Secondary aims include evaluation of FDG PET/CT or FDG PET/MRI's diagnostic accuracy of lymph node and distant metastases, their impact on TNM-staging, and PET uptake and volumetric parameters in pleural mesothelioma.
METHODS: We conducted a systematic review and meta-analysis adhering to 'Preferred Reporting Guidelines for Systematic reviews and Meta-Analyses' (PRISMA) with a predefined literature search. It consisted of the terms: "pleura" or "pleural" or "mesothelioma", "PET" or "positron emission tomography", and "FDG" or "fluorodeoxyglucose". Two independent reviewers systematically screened the literature based on eligibility criteria, extracted data, and evaluated quality of evidence. The meta-analysis was performed using a hierarchical model to estimate pooled diagnostic accuracy parameters. Publication bias was assessed with Deeks' regression test.
RESULTS: Forty-one studies were included; the primary aim was evaluated by a meta-analysis which included 10 studies. Thirty-eight studies were included for evaluating secondary aims. The estimated pooled sensitivity and specificity for FDG PET/CT in differentiating pleural mesothelioma from benign pleural lesions were 0.94 (95%CI: 0.87-0.97) and 0.84 (95%CI: 0.73-0.91), respectively. There was substantial study heterogeneity, but no publication bias was detected.
CONCLUSION: This study shows high sensitivity and specificity of FDG PET/CT for diagnosing pleural mesothelioma. The results are compatible with previous findings and give an updated evidence base to compare diagnostic performance of FDG PET/CT to other imaging modalities e.g. contrast-enhanced CT or PET with novel tracers.

Keywords: Diagnostic Accuracy; FDG PET/CT; FDG PET/MRI; Meta-analysis; Pleural mesothelioma

DOI: https://doi.org/10.1053/j.semnuclmed.2026.05.010

ERJ Open Res. 2026 May;pii: 01300-2025. [Epub ahead of print]12(3):

Ki67 proliferation index augments two-tier tumour grade in prediction of survival and progression-free survival in epithelioid pleural mesothelioma.

Geraldine A Lynch, Yu Zhi Zhang, Nidhi Bhatt, Pia Charters, Avinash Aujayeb, Saru Walker, Jenny Symonds, Amelia O Clive, Rahul Bhatnagar, Anna Morley, Paul White, Andrew G Nicholson, Nick A Maskell, Anna Bibby.

Background: Pleural mesothelioma (PM) is a fatal asbestos-related cancer with a poor and often uncertain prognosis. This study validates the histological proliferation marker Ki67 and evaluates whether its integration into the two-tier tumour grading system can improve prognostication in epithelioid PM.
Methods: Patients with epithelioid PM were recruited from two longitudinal cohort studies from 2010-2023. Diagnostic biopsies were analysed by three pulmonary pathologists. Cox regression determined the relationship between covariables and outcomes. Pearson correlation assessed the association between Ki67 and two-tier grade. A prognostic model combining Ki67 and tumour grade was internally validated using bootstrapping.
Results: 98 patients were recruited. Ki67 was strongly predictive of overall survival (OS) and progression-free survival (PFS) and correlated with two-tier tumour grade. 30% was the optimal cut-off, with Ki67 more strongly predictive of OS (hazard ratio (HR) 2.37, 95% CI 1.51-3.71) and PFS (HR 2.09, 1.35-3.23) than two-tier grade (HR 1.83, 1.13-2.97 and HR 1.70, 1.08-2.66, respectively). Combining Ki67 and two-tier grade improved prediction of OS and PFS compared with two-tier grade alone. Ki67 stratified patients within each tumour grade, with median survival in the lowest risk group (low Ki67, low grade) of 660.5 days (IQR 329-1297) and 300 days (IQR 124-366) in the highest risk group (high Ki67, high grade).
Conclusion: Ki67 is a valid surrogate for tumour grade with an optimal cut-off at 30%. Integrating Ki67 into the two-tier grading system enhances prognostic accuracy, improves outcome prediction and would reduce uncertainty for patients and clinicians.

DOI: https://doi.org/10.1183/23120541.01300-2025