Metabolic vulnerabilities in pleural mesothelioma

Our plain-English summary of Metabolic vulnerabilities in pleural mesothelioma, by S. Plans-Marin, C. Muñoz-Pinedo, E. Nadal (Oncogenesis, 2026).

The study

• Authors: S. Plans-Marin, C. Muñoz-Pinedo, E. Nadal
• Journal: Oncogenesis
• Published: 2026;15(1)
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a rare tumour of mesothelial origin that is often diagnosed at advanced stages. Despite recent approval of immunotherapy, the prognosis of mesothelioma remains dismal. Growing evidence links tumour metabolism to the molecular mechanisms driving mesothelioma's aggressiveness, therapeutic resistance and poor outcomes. Mesothelioma-specific metabolic alterations may be derived from asbestos-induced chronic inflammation, the mesothelial origin, the pleural microenvironment and tumour-stroma interactions, as well as recurrent genomic alterations that distinguish mesothelioma from malignancies of the lung parenchyma. Elucidating these metabolic alterations is therefore crucial for identifying exploitable vulnerabilities and improving therapeutic strategies. Key metabolic pathways, including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis and amino acid and lipid metabolism, are tightly interconnected within a dynamic network that regulates cell survival and proliferation. Metabolism also shapes tumour microenvironment by regulating redox homoeostasis, signalling and nutrient exchange. Considering these pathways in isolation provides an incomplete picture, and instead, studying them as a whole, and building a coherent metabolic map is essential for revealing context-specific dependencies. In this review, we summarise current knowledge of mesothelioma metabolism, highlighting how recurrent genetic alterations including CDKN2A, MTAP, BAP1, NF2 and TP53 influence metabolic phenotypes. We discuss experimental and therapeutic efforts that target individual metabolic branches and evaluate how these insights can inform a unified strategy to exploit metabolic weaknesses and guide the rational development of combination therapies.

© 2026. The Author(s).

In plain English

This was a review article, not a new study. The authors summarised published laboratory, animal and clinical research on how pleural mesothelioma cells use nutrients. They described asbestos exposure as the main driver of the disease. They focused on recurrent genetic alterations in CDKN2A, MTAP, BAP1, NF2 and TP53 that, according to the studies reviewed, change tumour metabolism. They noted that TP53 mutations are relatively uncommon, with p53 often inactivated through p14 loss. Their table of earlier trials listed overall survival of 12.1 versus 9.3 months for cisplatin plus pemetrexed versus cisplatin alone. It listed 9.3 versus 7.7 months when pegargiminase was added to chemotherapy in non-epithelioid, ASS1-deficient pleural mesothelioma. A cited retrospective cohort study found similar survival in pleural mesothelioma patients whether or not they took metformin for type 2 diabetes. They noted that blocking glutamine receptors or glutaminolysis enzymes remained preclinical. An older phase 2 trial of the broad glutamine antagonist DON produced no objective responses and considerable toxicity. The authors concluded that adding molecular and metabolic profiling to how patients are grouped for treatment may help improve outcomes.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research on mesothelioma metabolism
• Who was studied: No new patients or samples were studied. The review covers published cell-line, animal (xenograft) and clinical studies of pleural mesothelioma, with a focus on recurrent genetic alterations.
• Exposure: Not an exposure study. The authors describe occupational or environmental asbestos exposure as the main driver of pleural mesothelioma. Their focus is on tumour metabolic pathways and the drugs that target them.
• Main results:
  • Citing earlier work, the review states that CDKN2A homozygous deletions are found in up to 74% of pleural mesothelioma patients.
  • Citing earlier work, the review states that the MTAP gene is co-deleted in up to 91% of mesotheliomas.
  • Citing earlier work, the review states that BAP1 is mutated in up to 70% of epithelioid tumours.
  • The review states that TP53 mutations are relatively uncommon in mesothelioma. It adds that p53 is often functionally inactivated through the more common p14 loss.
  • In the review's summary table, the earlier EMPHACIS phase III trial reported overall survival of 12.1 versus 9.3 months (HR 0.77) for cisplatin plus pemetrexed versus cisplatin alone.
  • In the review's summary table, the earlier ATOMIC-Meso trial in non-epithelioid, ASS1-deficient pleural mesothelioma reported overall survival of 9.3 versus 7.7 months (HR 0.71, p = 0.02) with pemetrexed/platinum plus or minus pegargiminase (ADI-PEG 20).
  • Citing other work, the review states that with first-line immunotherapy only 16% of patients were alive at 4 years.
  • The review reports that a cited large retrospective cohort study found that patients with pleural mesothelioma receiving metformin for type 2 diabetes had survival similar to those who did not receive it.
  • The review reports that a phase 2 trial of the broad glutamine antagonist DON (6-diazo-5-oxo-L-norleucine) was run in patients with refractory sarcoma or mesothelioma. It failed to produce objective responses and showed considerable toxicity.
  • The review reports that statin treatment did not affect the development of mesothelioma in mice. It states that this was corroborated retrospectively with data from the Wittenoom cohort.
• The authors' conclusion: The authors concluded that integrating molecular and metabolic profiling into patient stratification may help improve outcomes and advance personalised treatment.
• Limitations the authors state:
  • The authors state they could not cite all the literature on the topic because of space constraints.
  • The authors note that inhibiting glutamine receptors or glutaminolysis enzymes remains at the preclinical stage.
  • The authors note that in vivo evidence is lacking for the suggested vulnerabilities of BAP1-deficient mesothelioma.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Immunotherapy, Prognosis, Chronic Inflammation, Parenchyma, CDKN2A, MTAP.

Related studies

• Integrated genomics point to immune vulnerabilities in pleural mesothelioma — A. Nastase, A. Mandal, et al. (2021)
• Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma — G.K. Pandey, N. Landman, et al. (2023)
• Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma — H. Yang, D. Xu, et al. (2020)
• Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight — D. Xu, H. Yang, et al. (2020)
• Therapeutic vulnerabilities exposed by the 9p21 loss identified through multiparametric drug screening inform rational combination strategies — R. Bevilacqua, P. Gasperini, et al. (2026)
• Insights Into Genomic Drivers, Transcriptomic Heterogeneity, and Therapeutic Vulnerabilities From Novel Mesothelioma Cell Lines — Y. Wu, F. Cao, et al. (2026)

Browse more research in Oncogenesis, or return to medical research.