Corticosteroid-refractory checkpoint inhibitor pneumonitis in lung cancer: biological heterogeneity and mechanism-informed management
Year: 2026
Type: article
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.
Source: Frontiers in Immunology
Authors: Rong Zhang, Xiaoxue Zhang, Xiulan He, Min Xiang
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7224123630