Immune checkpoint inhibitors (ICIs) are a key treatment for non-small cell lung cancer (NSCLC), but they can cause serious immune-related adverse events (irAEs), including checkpoint inhibitor pneumonitis (CIP), which is a major cause of mortality. CIP is characterized by lung inflammation and can lead to severe morbidity and mortality. The pathophysiology of CIP involves immune system activation, leading to T cell overactivation, cytokine dysregulation, and autoantibody production. CIP is associated with increased T cell activity, particularly CD4+ and CD8+ T cells, and the presence of Th17.1 cells, which are linked to autoimmune responses. The development of CIP is also influenced by genetic factors, such as HLA variations, and the tumor microenvironment. CIP can be triggered by various factors, including the use of PD-1/PD-L1 inhibitors, combination immunotherapy, and radiotherapy. The incidence of CIP varies, with real-world data showing higher rates than those observed in clinical trials. CIP is typically managed with corticosteroids, and in some cases, additional immunosuppressive therapy is required. However, rechallenge with ICIs after CIP resolution is limited. The mechanisms underlying CIP are not fully understood, and further research is needed to develop more effective treatments. Potential areas for future research include understanding the role of the microbiome, investigating the lung microbiome, and developing animal models to study CIP. The complexity of the immune system and the interactions between ICIs and the body's immune response make CIP a challenging condition to manage. Overall, while ICIs have revolutionized cancer treatment, their use is limited by the risk of immune-related toxicities, particularly CIP. Understanding the pathophysiology of CIP is crucial for improving patient outcomes and developing more effective treatment strategies.Immune checkpoint inhibitors (ICIs) are a key treatment for non-small cell lung cancer (NSCLC), but they can cause serious immune-related adverse events (irAEs), including checkpoint inhibitor pneumonitis (CIP), which is a major cause of mortality. CIP is characterized by lung inflammation and can lead to severe morbidity and mortality. The pathophysiology of CIP involves immune system activation, leading to T cell overactivation, cytokine dysregulation, and autoantibody production. CIP is associated with increased T cell activity, particularly CD4+ and CD8+ T cells, and the presence of Th17.1 cells, which are linked to autoimmune responses. The development of CIP is also influenced by genetic factors, such as HLA variations, and the tumor microenvironment. CIP can be triggered by various factors, including the use of PD-1/PD-L1 inhibitors, combination immunotherapy, and radiotherapy. The incidence of CIP varies, with real-world data showing higher rates than those observed in clinical trials. CIP is typically managed with corticosteroids, and in some cases, additional immunosuppressive therapy is required. However, rechallenge with ICIs after CIP resolution is limited. The mechanisms underlying CIP are not fully understood, and further research is needed to develop more effective treatments. Potential areas for future research include understanding the role of the microbiome, investigating the lung microbiome, and developing animal models to study CIP. The complexity of the immune system and the interactions between ICIs and the body's immune response make CIP a challenging condition to manage. Overall, while ICIs have revolutionized cancer treatment, their use is limited by the risk of immune-related toxicities, particularly CIP. Understanding the pathophysiology of CIP is crucial for improving patient outcomes and developing more effective treatment strategies.