Immunotherapy has transformed the treatment landscape for a wide range of human malignancies. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block the immune regulatory “checkpoint” receptors, the Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), Programmed Cell Death 1 (PD-1), or its ligand PD- L1. ICIs produce durable responses in many patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs), such as diabetic ketoacidosis (DKA) or thyroid disease, appearing to occur more frequently than originally expected. Immunotoxicity from cancer immunotherapy occurs in up to 90%, whereas autoimmune endocrine diseases occur in approximately 50% of patients treated with antibodies to CTLA-4 and/or PD-1/PD-L1. These irAEs can be serious or even life- threatening, such as autoimmune type 1 diabetes (T1D) presenting in DKA, and primary adrenal insufficiency caused by autoimmune adrenalitis. A recent study showed a marked increase of ICI-related autoimmune diabetes; reported in over 50% of the patients, with half of these patients presenting in DKA (50.2%). Thus, reliable biomarkers are needed to accurately stratify the risk of irAEs in patients who are candidates for these therapies (Aim I); these biomarkers may point to novel molecular pathways that could be targeted to prevent irAEs caused by immune checkpoint blockade (Aim II). Specifically, we will utilize the state-of-the-art single-cell platforms to investigate and characterize the comprehensive phenotypic and functional analyses of systemic cellular networks in patients with ICI-induced endocrinopathies. Our studies are greatly facilitated by the Baylor College of Medicine Immunotoxicity Working Group. Understanding the immunologic factors and the biomarkers associated with ICI-mediated inflammatory toxicities will be useful for the identification and early treatment of ICI-induced irAEs, and it may provide new insights into the pathoetiology and treatment of autoimmune endocrine diseases.