Corticosteroid-refractory checkpoint inhibitor pneumonitis in lung cancer: biological heterogeneity and mechanism-informed management
- 1Department of Respiratory and Critical Care Medicine, West China Tianfu Hospital, Sichuan University
- 2Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the treatment of lung cancer, but checkpoint inhibitor pneumonitis (CIP) remains a potentially life-threatening immune-related adverse event. A subset of patients fails to improve despite adequate glucocorticoid therapy and develops corticosteroid-refractory CIP, which is associated with respiratory failure, substantial mortality, and considerable therapeutic uncertainty. This review critically examines the clinical definition, phenotypic characteristics, immunological mechanisms, and therapeutic evidence for corticosteroid-refractory CIP. Emerging data suggest that refractoriness should not be regarded as a uniform failure of glucocorticoid treatment, but rather as a biologically heterogeneous and dynamically evolving syndrome involving persistent tissue-resident T-cell activation, inflammatory T-cell–myeloid crosstalk, cytokine-network redundancy, innate immune dysregulation, and, in some patients, transition toward maladaptive tissue repair and structural lung remodeling. Current second-line treatments, including mycophenolate mofetil, infliximab, intravenous immunoglobulin, tocilizumab, cyclophosphamide, and calcineurin inhibitors, are supported predominantly by retrospective studies and case-report and case-series evidence, with no established optimal treatment sequence. We therefore propose a hypothesis-generating phenotype-to-therapy framework that distinguishes lymphocyte-dominant, cytokine-dominant, fulminant acute lung injury/diffuse alveolar damage, innate/myeloid-dominant, and organizing/fibrotic-remodeling phenotypes while recognizing their potential overlap and temporal evolution. Translating this framework into clinical practice will require harmonized definitions, longitudinal multimodal phenotyping, treatment-predictive biomarkers, and prospective comparative studies. Ultimately, management should move beyond empirical escalation of immunosuppression toward identifying the dominant biological process at a given disease stage and matching treatment intensity and mechanism accordingly.
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BibTeX
@article{zhang2026corticosteroidrefractory,
title = {{Corticosteroid-refractory checkpoint inhibitor pneumonitis in lung cancer: biological heterogeneity and mechanism-informed management}},
author = {Rong Zhang and Xiaoxue Zhang and Xiulan He and Min Xiang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1983756},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1983756/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Corticosteroid-refractory checkpoint inhibitor pneumonitis in lung cancer: biological heterogeneity and mechanism-informed management
AU - Rong Zhang
AU - Xiaoxue Zhang
AU - Xiulan He
AU - Min Xiang
PY - 2026
DA - 2026/10/28
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1983756
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1983756/full
AB - Immune checkpoint inhibitors (ICIs) have transformed the treatment of lung cancer, but checkpoint inhibitor pneumonitis (CIP) remains a potentially life-threatening immune-related adverse event. A subset of patients fails to improve despite adequate glucocorticoid therapy and develops corticosteroid-refractory CIP, which is associated with respiratory failure, substantial mortality, and considerable therapeutic uncertainty. This review critically examines the clinical definition, phenotypic characteristics, immunological mechanisms, and therapeutic evidence for corticosteroid-refractory CIP. Emerging data suggest that refractoriness should not be regarded as a uniform failure of glucocorticoid treatment, but rather as a biologically heterogeneous and dynamically evolving syndrome involving persistent tissue-resident T-cell activation, inflammatory T-cell–myeloid crosstalk, cytokine-network redundancy, innate immune dysregulation, and, in some patients, transition toward maladaptive tissue repair and structural lung remodeling. Current second-line treatments, including mycophenolate mofetil, infliximab, intravenous immunoglobulin, tocilizumab, cyclophosphamide, and calcineurin inhibitors, are supported predominantly by retrospective studies and case-report and case-series evidence, with no established optimal treatment sequence. We therefore propose a hypothesis-generating phenotype-to-therapy framework that distinguishes lymphocyte-dominant, cytokine-dominant, fulminant acute lung injury/diffuse alveolar damage, innate/myeloid-dominant, and organizing/fibrotic-remodeling phenotypes while recognizing their potential overlap and temporal evolution. Translating this framework into clinical practice will require harmonized definitions, longitudinal multimodal phenotyping, treatment-predictive biomarkers, and prospective comparative studies. Ultimately, management should move beyond empirical escalation of immunosuppression toward identifying the dominant biological process at a given disease stage and matching treatment intensity and mechanism accordingly.
SN - 1664-3224
ER -