Toxicity in the era of immune checkpoint inhibitor therapy Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by blocking co-inhibitory immune checkpoint molecules such as PD-1 and CTLA-4. Although ICIs have been highly effective in treating various cancers, they often cause off-target inflammation, leading to immune-related adverse events (irAEs). These irAEs can affect multiple organs and often require corticosteroids or cessation of ICI therapy, which can worsen cancer outcomes. The molecular and immune mechanisms underlying irAEs are not fully understood, and there is a need for preclinical models to better understand and manage these events. This review discusses current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis, along with their management. The review also explores the mechanisms of immune checkpoints in regulating immunity, the role of ICIs in cancer treatment, and the adverse events associated with ICI therapy. Immune checkpoints, such as PD-1 and CTLA-4, regulate immune responses by inhibiting T cell activation. ICIs block these checkpoints, leading to enhanced T cell activation and potentially causing irAEs. The review highlights the mechanisms of ICI-induced toxicity, including dermatologic toxicity, colitis, neurologic dysfunction, and endocrine dysfunction. It also discusses the role of the gut microbiome in ICI-induced colitis and the importance of monitoring thyroid function in patients receiving ICI therapy. The review emphasizes the need for further research to understand the mechanisms of ICI-induced toxicity and to develop safe and effective therapeutic strategies. It also highlights the importance of clinical trials and preclinical studies in understanding the mechanisms of ICI-induced toxicity and in developing effective treatments for these adverse events.Toxicity in the era of immune checkpoint inhibitor therapy Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by blocking co-inhibitory immune checkpoint molecules such as PD-1 and CTLA-4. Although ICIs have been highly effective in treating various cancers, they often cause off-target inflammation, leading to immune-related adverse events (irAEs). These irAEs can affect multiple organs and often require corticosteroids or cessation of ICI therapy, which can worsen cancer outcomes. The molecular and immune mechanisms underlying irAEs are not fully understood, and there is a need for preclinical models to better understand and manage these events. This review discusses current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis, along with their management. The review also explores the mechanisms of immune checkpoints in regulating immunity, the role of ICIs in cancer treatment, and the adverse events associated with ICI therapy. Immune checkpoints, such as PD-1 and CTLA-4, regulate immune responses by inhibiting T cell activation. ICIs block these checkpoints, leading to enhanced T cell activation and potentially causing irAEs. The review highlights the mechanisms of ICI-induced toxicity, including dermatologic toxicity, colitis, neurologic dysfunction, and endocrine dysfunction. It also discusses the role of the gut microbiome in ICI-induced colitis and the importance of monitoring thyroid function in patients receiving ICI therapy. The review emphasizes the need for further research to understand the mechanisms of ICI-induced toxicity and to develop safe and effective therapeutic strategies. It also highlights the importance of clinical trials and preclinical studies in understanding the mechanisms of ICI-induced toxicity and in developing effective treatments for these adverse events.