CRAC channels as targets for immunotherapy.

Ca²⁺ release-activated Ca²⁺ (CRAC) channels facilitate store-operated Ca²⁺ entry in both immune and nonimmune cells. They are crucial for the function of many immune cell types and strongly associated with the pathophysiology of immune-related disorders. Inherited null mutations in the genes encoding the CRAC channel, ORAI1, and its activator STIM1, are linked to inborn errors of immunity in patients, highlighting the essential role of these channels in immunity. Preclinical studies using knockout mice and CRAC channel inhibitors (CRACi) have further demonstrated their pivotal function in the pathophysiology of immune-related conditions, including immunity to infection, autoimmunity, allergy, and other inflammatory diseases. Clinical trials in patients with inflammatory disorders underscore the potential utility of CRACi for immunotherapy. Here, we provide an overview of CRAC channels in immune cell function, review their roles in preclinical models of immune diseases, and discuss the outcomes of clinical trials involving CRACi.