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Life sciences · Journal article
Frontiers in Immunology · October 28, 2026
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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.