Abstract

Immune checkpoint inhibitors (ICI) therapy based on programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC) and improved the survival expectancy of patients. However, it also leads to immune-related adverse events (iRAEs), which result in multiple organ damage. Among them, the most common one with the highest mortality in NSCLC patients treated with ICI is checkpoint inhibitor pneumonitis (CIP). The respiratory signs of CIP are highly coincident and overlap with those in primary lung cancer, which causes difficulties in detecting, diagnosing, managing, and treating. In clinical management, patients with serious CIP should receive immunosuppressive treatment and even discontinue immunotherapy, which impairs the clinical benefits of ICIs and potentially results in tumor recrudesce. Therefore, accurate diagnosis, detailedly dissecting the pathogenesis, and developing reasonable treatment strategies for CIP are essential to prolong patient survival and expand the application of ICI. Herein, we first summarized the diagnosis strategies of CIP in NSCLC, including the classical radiology examination and the rising serological test, pathology test, and artificial intelligence aids. Then, we dissected the potential pathogenic mechanisms of CIP, including disordered T cell subsets, the increase of autoantibodies, cross-antigens reactivity, and the potential role of other immune cells. Moreover, we explored therapeutic approaches beyond first-line steroid therapy and future direction based on targeted signaling pathways. Finally, we discussed the current impediments, future trends, and challenges in fighting ICI-related pneumonitis.

MeSH

Cells, Lung, Neoplasms, Carcinoma, Non-Small-Cell Lung, Immune Checkpoint Inhibitors, Lung Neoplasms, Immune System Diseases, Small Cell Lung Carcinoma, Diagnosis, Therapeutics, Cell Death

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• Real-World Insights into the Impact of Durvalumab on Stage III Unresectable Non-Small Cell Lung Cancer-A Narrative Review. Cancers (Basel), 2025
• Immune-related adverse events with PD-1/PD-L1 inhibitors: insights from a real-world cohort of 2523 patients. Front Pharmacol, 2025
• A Thorough Review of the Clinical Applications of Artificial Intelligence in Lung Cancer. Cancers (Basel), 2025
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• Antibiotic Use and Survival in Patients With Late-Stage NSCLC Treated With Chemoimmunotherapy. JTO Clin Res Rep, 2024
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• Lower respiratory tract microbiome is associated with checkpoint inhibitor pneumonitis in lung cancer patients. Transl Lung Cancer Res, 2024
• Clinical management of checkpoint inhibitor pneumonitis: Focus, challenges, and future directions. Chin Med J Pulm Crit Care Med, 2025