This review comprehensively examines the pathogenic mechanisms and clinical manifestations of immune-related adverse events (irAEs) resulting from the loss of self-tolerance due to Immune Checkpoint Inhibitors (ICIs). ICIs, which include CTLA4 and PD1/PD-L1 inhibitors, have revolutionized cancer treatment by enhancing anti-tumor immune responses. However, they also pose a risk of developing irAEs, which can affect various organs and systems. The review discusses the incidence, risk factors, and clinical manifestations of irAEs, categorized by organ types. It highlights the differences in the frequency and nature of irAEs between CTLA4 and PD1/PD-L1 inhibitors, and the intricate differential with primary autoimmune disorders. The review also explores the biological mechanisms underlying irAEs, including the modulation of T-cell and B-cell responses, autoantigen cross-reactivity, and the impact of host-specific factors such as genetics, microbiota, and pre-existing autoimmune conditions. Additionally, it emphasizes the importance of early identification and management of irAEs to prevent severe complications and improve patient outcomes. The review concludes by highlighting the need for further research, including the development of biomarkers and enhanced education for clinicians and patients, to address the challenges posed by irAEs in cancer immunotherapy.This review comprehensively examines the pathogenic mechanisms and clinical manifestations of immune-related adverse events (irAEs) resulting from the loss of self-tolerance due to Immune Checkpoint Inhibitors (ICIs). ICIs, which include CTLA4 and PD1/PD-L1 inhibitors, have revolutionized cancer treatment by enhancing anti-tumor immune responses. However, they also pose a risk of developing irAEs, which can affect various organs and systems. The review discusses the incidence, risk factors, and clinical manifestations of irAEs, categorized by organ types. It highlights the differences in the frequency and nature of irAEs between CTLA4 and PD1/PD-L1 inhibitors, and the intricate differential with primary autoimmune disorders. The review also explores the biological mechanisms underlying irAEs, including the modulation of T-cell and B-cell responses, autoantigen cross-reactivity, and the impact of host-specific factors such as genetics, microbiota, and pre-existing autoimmune conditions. Additionally, it emphasizes the importance of early identification and management of irAEs to prevent severe complications and improve patient outcomes. The review concludes by highlighting the need for further research, including the development of biomarkers and enhanced education for clinicians and patients, to address the challenges posed by irAEs in cancer immunotherapy.