The role of microRNAs and competing endogenous RNA regulatory networks in mesothelioma response to immunotherapy

Lung Cancer 2026 July [Link]

Farhad Kosari, Paul Baas, Maria Disselhorst, Kim Lauer, Tobias Peikert, Stephen Murphy, Janet Schaefer Klein, Aaron S Mansfield

Abstract

Assessing the contributions of microRNAs to gene expression regulation and treatment outcomes in malignancies is challenging. Traditional analyses focus on individual microRNAs, overlooking competitive binding among RNA species sharing common microRNAs. We evaluated the impact of microRNA’s impact on the survival of patients with mesothelioma in response to treatment with immune checkpoint inhibitors (ICI) within the context of competing endogenous RNA (ceRNA) networks. Using two large public mesothelioma datasets, we constructed ceRNA networks (ceRNETs) and analyzed differentially expressed microRNAs in patients with favorable versus unfavorable survival outcomes from two ICI mesothelioma trials. ceRNETs from public and trial cohorts were largely consistent. Notably, tumors with favorable survival outcomes exhibited overexpressed microRNAs targeting ceRNETs with co-regulated gene expression profiles. These downregulated profiles are often linked to ICI resistance. Crosstalk among ceRNETs appeared coordinated, forming part of an existing mesothelioma regulatory network. Furthermore, in response to ICI this regulatory network was tipped towards downregulation of immune suppressive pathways in patients with the favorable outcomes. Our findings suggest that ceRNET-based analysis elucidates the immunologic context of cancers and may have prognostic significance for patients who receive ICI. These findings may also uncover novel therapeutic strategies, including delivery of immunoregulatory microRNAs frequently lost in mesothelioma.