bims-mesote 2026-01-04 papers

Issue of 2026–01–04
three papers selected by
Laura Mannarino, Humanitas Research

Cancers (Basel). 2025 Dec 17. pii: 4020. [Epub ahead of print]17(24):

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

Martina Delsignore, Gaia Cassinari, Simona Revello, Luigi Cerbone, Federica Grosso, Marcello Arsura, Chiara Porta.

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.

Keywords: cell therapies; epigenetic modulators; immune infiltrate; immunotherapy; microbiota; oncolytic virus; pleural mesothelioma; predictive biomarkers; tumor microenvironment; vaccine

DOI: https://doi.org/10.3390/cancers17244020

Int J Cancer. 2025 Dec 30.

Integrating polygenic and methylation risk scores for pleural mesothelioma risk stratification.

Pleural mesothelioma (PM) is a lethal cancer primarily caused by asbestos exposure. Not all exposed individuals develop PM, suggesting the involvement of additional factors. This underscores the need for robust predictive models integrating biomarkers from multi-omic domains to improve risk stratification and early detection. We developed and evaluated polygenic risk scores (PRS) and methylation risk scores (MRS) using a retrospective case-control study (749 participants: 387 PM cases, 362 controls) and a nested case-control European Prospective Investigation into Cancer and Nutrition (EPIC)-Meso study (268 participants: 134 preclinical PM cases, 134 matched controls) within the EPIC cohort. Genome-wide association analyses in the retrospective case-control study identified PM-associated variants. The PRS (1123 SNPs with p < 0.001) in the retrospective training subset stratified disease risk in the test set (ORs 3.46-9.54 across top percentiles) and improved model discrimination (AUC = 0.75 vs. 0.71 in baseline model, p = 0.04). In EPIC-Meso, PRS performance was limited (AUC = 0.52). External validation in the UK-Biobank (UKBB) confirmed a modest but consistent association with PM-risk. A Meta-PRS derived from the UKBB-FinnGen meta-analysis replicated this trend in the full retrospective dataset, showing higher OR across top percentiles (2.5-12.3) and improved discrimination (AUC 0.74 vs. 0.72, p = 0.016). MRS, with 68 differentially methylated CpGs (effect-size >|0.10|, FDR p < 0.05) in the retrospective training set, increased the AUC from 0.66 to 0.85 (p < 0.001) in the test set and from 0.51 to 0.62 in EPIC-Meso. PRS was most predictive in low-exposure groups, while MRS remained robust across exposure levels. Combined PRS-MRS models improved discrimination. Integrating multi-omic biomarkers can enhance PM-risk stratification and support earlier, targeted interventions in high-risk asbestos-exposed groups.

Keywords: genome‐wide association analyses (GWAS); methylation risk score (MRS); pleural mesothelioma (PM); polygenic risk score (PRS); risk assessment

DOI: https://doi.org/10.1002/ijc.70316

medRxiv. 2025 Sep 25. pii: 2025.09.23.25336488. [Epub ahead of print]

Urinary Metabolites and Survival in Malignant Mesothelioma.

Leila Toulabi, Joshua K Stone, Mohammed Khan, Daxesh P Patel, Raffit Hassan, Curtis C Harris.

Background: Malignant mesothelioma is a rare and aggressive malignancy with limited treatment options and poor survival outcomes. Current biomarkers such as MESOMARK, fibulin-3, and osteopontin show diagnostic potential but remain hampered by inconsistent sensitivity and reproducibility. Urine-based metabolites may provide a simple, noninvasive alternative for prognosis and disease monitoring.
Methods: We evaluated whether four urinary metabolites-creatine riboside, N-acetylneuraminic acid, cortisol sulfate, and cholestane pentol-previously associated with prognosis in lung and liver cancer, are prognostic in mesothelioma. Urinary metabolite concentrations were quantified in a clinically annotated cohort with survival follow-up. Associations with overall survival and a validated poor-prognostic gene expression signature were analyzed.
Results: Elevated urinary concentrations of the four metabolites were significantly correlated with poor-prognostic gene expression profiles. Patient survival declined progressively with the number of elevated metabolites, with the poorest outcomes observed in individuals harboring three or more high metabolites. These associations were independent of clinical variables and consistent in sensitivity analyses, suggesting that metabolite elevations reflect aggressive tumor biology.
Interpretation: Urinary metabolites represent promising prognostic biomarkers in mesothelioma. Their additive and dose-dependent relationship with survival highlights their potential clinical utility for risk stratification, patient monitoring, and trial design. Because urine collection is noninvasive and repeatable, these biomarkers could complement existing blood-based assays and provide an accessible tool for clinical practice. Larger, multi-institutional studies are warranted to validate their prognostic significance and enable translation into patient care.

DOI: https://doi.org/10.1101/2025.09.23.25336488