Cytotoxic T lymphocytes (CTLs) and natural killer (NK)cells contribute to the body’s immune defenses.Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases.Although CAR-modified NK cell immunotherapy is rapidly gaining attention,its clinical applications are mainly focused on preclinical investigations using the NK92 cell line.Despite recent advances in CAR-modified T cell immunotherapy,cost and severe toxicity have hindered its widespread use.To alleviate these disadvantages of CAR-modified T cell immunotherapy,additional cytotoxic cell-mediated immunotherapies are urgently needed.The unique biology of NK cells allows them to serve as a safe,effective,altative immunotherapeutic strategy to CAR-modified T cells in the clinic.While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood,the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential.The role of the IS in CAR T and NK cell immunotherapies will allow scientists to hess the power of CAR-modified T and NK cells to treat cancer and infectious diseases.In this review,we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV),and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy,as well as the importance of understanding the molecular mechanisms of CAR-modified T cell-or NK cell-mediated cytotoxicity and side effects,with a focus on the CAR-modified NK cell IS.