Determinants of Response to Immune Checkpoint Blockade in Pleural Mesothelioma: Molecular, Immunological, and Clinical Perspectives

Our plain-English summary of Determinants of Response to Immune Checkpoint Blockade in Pleural Mesothelioma: Molecular, Immunological, and Clinical Perspectives, by M. Delsignore, G. Cassinari, S. Revello, et al (Cancers, 2025).

The study

• Authors: M. Delsignore, G. Cassinari, S. Revello, L. Cerbone, F. Grosso, M. Arsura, C. Porta
• Journal: Cancers
• Published: 2025;17(24)
• Type of article: Review
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)-notably the combination of anti-PD-1 and anti-CTLA-4 therapies-clinical responses remain variable and overall survival gains modest. Consequently, there is an urgent need for multidimensional biomarkers and adaptive trial designs to unravel the complexity of PM immune biology. This review provides a comprehensive overview of current evidence on how histological subtypes (epithelioid vs. non-epithelioid) influence ICB efficacy, highlighting distinct genetic landscapes (e.g., BAP1, CDKN2A, NF2 mutations) and tumor microenvironment (TME) features, including immune infiltration patterns and PD-L1 or VISTA expression, that underlie differential responses. We further examine intrinsic tumor factors-such as mutational burden and checkpoint ligand expression-and extrinsic determinants, including immune cell composition, stromal architecture, patient immune status, and microbiota, as modulators of immunotherapy outcomes. We also discuss the rationale behind emerging strategies designed to enhance ICB efficacy, currently under clinical evaluation. These include combination regimens with chemotherapy, radiotherapy, surgery, epigenetic modulators, anti-angiogenic agents, and novel immunotherapies such as next-generation checkpoint inhibitors (LAG-3, VISTA), immune-suppressive cell-targeting agents, vaccines, cell-based therapies, and oncolytic viruses. Collectively, these advancements underscore the importance of integrating histological classification with molecular and microenvironmental profiling to refine patient selection and guide the development of combination strategies aimed at transforming "cold" mesotheliomas into "hot," immune-responsive tumors, thereby enhancing the efficacy of ICB.

In plain English

This article is a narrative review, not a new study. The authors searched PubMed/MEDLINE, Scopus, Web of Science and ClinicalTrials.gov for records from 1 January 2020 to 9 November 2025. They looked for evidence on what influences response to immune checkpoint blockade, a type of immunotherapy, in diffuse pleural mesothelioma. The review did not study asbestos exposure. It summarized trials run by other researchers. As the authors reported it, the CheckMate 743 trial found a median overall survival of 18.1 months with nivolumab plus ipilimumab versus 14.1 months with chemotherapy. In patients with sarcomatoid or biphasic (non-epithelioid) tumors the figures were 18.1 versus 8.8 months, and in epithelioid tumors 18.7 versus 16.5 months. The review also described reported differences between subtypes in gene alterations such as CDKN2A and in PD-L1 expression. It noted that in CheckMate 743 neither PD-L1 level nor tumor mutational burden clearly identified who benefited. The authors concluded that histological subtype is a major determinant of immunotherapy response and that no single biomarker adequately predicts response. They acknowledged bias inherent in narrative reviews.

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, scope-restricted literature review
• Who was studied: Published studies and registered trials on pleural mesothelioma and immune checkpoint inhibitors, found in PubMed/MEDLINE, Scopus, Web of Science Core Collection and ClinicalTrials.gov, dated 1 January 2020 to 9 November 2025
• Exposure: Not an asbestos exposure study. The subject is treatment with immune checkpoint blockade, notably anti-PD-1 plus anti-CTLA-4 therapy (nivolumab plus ipilimumab), and combinations under study. The introduction mentions the link to asbestos only as background from another source.
• Main results:
  • As reviewed: in the CheckMate 743 trial (unresectable pleural mesothelioma), median overall survival was 18.1 months with nivolumab plus ipilimumab vs. 14.1 months with chemotherapy (HR 0.74, p = 0.002)
  • As reviewed: in CheckMate 743, patients with sarcomatoid or biphasic mesothelioma had median overall survival of 18.1 months with nivolumab plus ipilimumab vs. 8.8 months with chemotherapy (HR about 0.46). For epithelioid patients the figures were 18.7 vs. 16.5 months (HR about 0.86).
  • As reviewed: in a cited study comparing 105 non-epithelioid with 235 epithelioid pleural mesotheliomas, alterations were more frequent in the non-epithelioid group, including CDKN2A (68% vs. 44%), CDKN2B (59% vs. 38%) and MTAP (51% vs. 29%)
  • As reviewed: immunohistochemical analyses showed sarcomatoid and biphasic tumors were 4 to 5 times more likely to express PD-L1 than epithelioid tumors
  • As reviewed: in CheckMate 743, PD-L1 expression (1% or more vs. less than 1%) did not significantly distinguish which patients benefited from immune checkpoint blockade
  • As reviewed: CheckMate 743 found no clear correlation between tumor mutational burden and benefit from nivolumab plus ipilimumab
• The authors' conclusion: The authors concluded that histological subtype is a major determinant of response to immunotherapy. They wrote that non-epithelioid tumors gain the most from dual checkpoint blockade while epithelioid tumors gain only a modest advantage, and that no single biomarker adequately predicts response.
• Limitations the authors state:
  • The authors acknowledged bias inherent in narrative review designs, which they tried to reduce by prioritizing prospective cohorts and histology-resolved analyses
  • The authors cautioned that the PD-L1 findings they reviewed were based mainly on archival diagnostic biopsies, which may not reflect changes in expression during disease progression

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, CTLA-4, Overall Survival, Biomarker, Histological Subtype, Epithelioid, Non-epithelioid, BAP1.

Related studies

• Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge — L. Calabrò, A. Morra, et al. (2018)
• Exceptional response of radiotherapy-naïve cranial meningiomas to dual immune checkpoint blockade in BAP1 tumor predisposition syndrome — G.L. Gallia, C.L. Hann, et al. (2026)
• Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy — J. Harber, T. Kamata, et al. (2021)
• Combination immune checkpoint blockade as an effective therapy for mesothelioma — V.S. Fear, C. Tilsed, et al. (2018)
• Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC — F. Facchinetti, A. Marabelle, et al. (2016)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)

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