ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1666946
Exosomal miRNA-148b/301a/423 Cluster Predicts Pneumonitis Risk in NSCLC with Concurrent Radiotherapy with immunotherapy via PTPN14-YAP signaling: A retrospective cohort study
Provisionally accepted
- 1The First Hospital of China Medical University, Shenyang, China
- 2Shenyang Fifth People’s Hospital, Shenyang, China
- 3Hebei University of Engineering, Handan, China
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Background: Radiotherapy (RT) combined with Immune checkpoint inhibitors (ICIs) significantly improve outcomes in non-small cell lung cancer (NSCLC), yet this combination amplifies treatment-related pneumonitis risk. The real-world incidence, predictive biomarkers, and underlying pathogenesis of RT-ICI-associated pneumonitis remain inadequately defined. Methods: We conducted a retrospective cohort study using electronic health records from 21,671 NSCLC patients treated with thoracic RT, categorized into RT-ICI (n = 8,744) and RT-nonICI (n =12,927) groups after 1:1 propensity score matching. Pneumonitis was diagnosed via clinical/imaging criteria and infection exclusion. Incidence of pneumonitis was evaluated using propensity score–matched analysis, Kaplan-Meier curves, and Cox regression models. Subgroup analyses were performed across demographic and clinical variables. Serum exosomes from 20 patients (10 per group) underwent miRNA sequencing. LASSO regression for biomarker modeling, single cell RNA-seq analysis and single-sample gene set enrichment analysis for function enrichment, then validated in vitro. Results: The incidence of pneumonitis was significantly higher in the RT-ICI group (28.9%) compared to the RT-nonICI group (10.0%) (hazard ratio [HR] = 2.86; 95% confidence interval [CI], 2.43–3.29; P < 0.001). This elevated risk persisted across age, sex, BMI, comorbidities, and autoimmune status. We identified a serum exosomal miRNA cluster (miR-148b-3p, miR-301a-3p, miR-423-3p) predictive of pneumonitis and poor survival. These miRNAs directly co-target to PTPN14, and crosstalk with fibrosis via TNF signal at single-cell level. Then we validated the This is a provisional file, not the final typeset article miRNA cluster suppressed PTPN14, activating YAP signal to promote EMT in pulmonary epithelial cell lines. Conclusions: RT-ICI therapy significantly increases pneumonitis risk in NSCLC, especially in autoimmune comorbidities. A serum exosomal miRNA cluster (miR-148b-3p/301a-3p/423-3p) enables early pneumonitis prediction and prognosis assessment, offering novel targets for prevention and monitoring.
Keywords: Non-small cell lung cancer, Radiotherapy, Immunotherapy, Pneumonitis, miRNA cluster
Received: 18 Jul 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Cao, Zhang, Zhao, Zhou and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Chang Zheng, The First Hospital of China Medical University, Shenyang, China
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