Cytokine release syndrome (CRS) is a serious adverse effect of T cell-engaging immunotherapies, including bispecific T-cell engaging (BiTE) antibodies and chimeric antigen receptor (CAR) T cells. It is characterized by a systemic inflammatory response, often leading to life-threatening complications. CRS can occur after various immunotherapies, including anti-T-cell antibodies, CD28 superagonists, and certain cancer drugs. It is also associated with severe viral infections and graft-versus-host disease. The pathophysiology of CRS involves the activation of T cells and bystander immune cells, leading to the release of cytokines such as IL-6, IFN-γ, and TNF-α. This results in a cytokine storm, which can cause multi-organ failure, vasopressor-requiring shock, and neurological complications. CRS is a common and potentially fatal complication of CAR T cell therapy, with up to 100% of patients experiencing CRS in clinical trials. The severity of CRS is influenced by factors such as the type of immunotherapy, the patient's underlying disease, and the dose of the treatment. The management of CRS involves a graded approach, with treatment options including IL-6 inhibitors like tocilizumab, corticosteroids, and other immunosuppressants. Tocilizumab is currently the gold standard for treating severe CRS, as it effectively reduces cytokine levels and improves symptoms. However, corticosteroids are generally avoided in CAR T cell therapy due to their potential to reduce the effectiveness of the treatment. The clinical presentation of CRS ranges from mild flu-like symptoms to severe life-threatening manifestations. It can mimic other conditions such as tumor lysis syndrome, sepsis, and hemophagocytic lymphohistiocytosis (HLH). Differential diagnosis is crucial to ensure appropriate treatment. CRS is often managed in intensive care settings, with close monitoring and supportive care. Preventive strategies, such as dose adjustment and premedication, are also important in reducing the risk of severe CRS. Future research aims to improve the diagnosis and treatment of CRS through the development of biomarkers and more targeted therapies. Advances in CAR T cell design, including conditional activation and suicide switches, may reduce the risk of CRS. Overall, understanding the mechanisms of CRS and improving treatment strategies are essential to enhance the safety and efficacy of immunotherapy.Cytokine release syndrome (CRS) is a serious adverse effect of T cell-engaging immunotherapies, including bispecific T-cell engaging (BiTE) antibodies and chimeric antigen receptor (CAR) T cells. It is characterized by a systemic inflammatory response, often leading to life-threatening complications. CRS can occur after various immunotherapies, including anti-T-cell antibodies, CD28 superagonists, and certain cancer drugs. It is also associated with severe viral infections and graft-versus-host disease. The pathophysiology of CRS involves the activation of T cells and bystander immune cells, leading to the release of cytokines such as IL-6, IFN-γ, and TNF-α. This results in a cytokine storm, which can cause multi-organ failure, vasopressor-requiring shock, and neurological complications. CRS is a common and potentially fatal complication of CAR T cell therapy, with up to 100% of patients experiencing CRS in clinical trials. The severity of CRS is influenced by factors such as the type of immunotherapy, the patient's underlying disease, and the dose of the treatment. The management of CRS involves a graded approach, with treatment options including IL-6 inhibitors like tocilizumab, corticosteroids, and other immunosuppressants. Tocilizumab is currently the gold standard for treating severe CRS, as it effectively reduces cytokine levels and improves symptoms. However, corticosteroids are generally avoided in CAR T cell therapy due to their potential to reduce the effectiveness of the treatment. The clinical presentation of CRS ranges from mild flu-like symptoms to severe life-threatening manifestations. It can mimic other conditions such as tumor lysis syndrome, sepsis, and hemophagocytic lymphohistiocytosis (HLH). Differential diagnosis is crucial to ensure appropriate treatment. CRS is often managed in intensive care settings, with close monitoring and supportive care. Preventive strategies, such as dose adjustment and premedication, are also important in reducing the risk of severe CRS. Future research aims to improve the diagnosis and treatment of CRS through the development of biomarkers and more targeted therapies. Advances in CAR T cell design, including conditional activation and suicide switches, may reduce the risk of CRS. Overall, understanding the mechanisms of CRS and improving treatment strategies are essential to enhance the safety and efficacy of immunotherapy.