ITPR3 encodes the type 3 inositol 1,4,5-trisphosphate receptor (IP3R3), a calcium channel localized to the endoplasmic reticulum membrane 1. Upon IP3 binding, ITPR3 transports calcium from the endoplasmic reticulum lumen to the cytoplasm, progressing through conformational states that increase calcium affinity and promote channel opening 2. Calcium binding to the cytoplasmic domain then stabilizes an inhibited state to terminate release, maintaining cellular calcium homeostasis 3. ITPR3 is critical for T cell calcium signaling and immune function. Dominant-negative variants impair store-operated calcium entry required for T cell activation, causing combined immunodeficiency characterized by T cell lymphopenia and defective NF-κB and NFAT-mediated responses 1. ITPR3 variants also cause Charcot-Marie-Tooth disease, an intermediate demyelinating neuropathy, likely through nodal dysfunction in Schwann cells 4. In cancer, ITPR3 upregulation promotes pathogenesis through multiple mechanisms: pancreatic cancer patients with elevated ITPR3 show worse survival and it serves as an independent prognostic factor 5; in colorectal cancer, ITPR3 drives metastatic liver colonization via the ITPR3/calcium/RELB axis 6; and in metabolic-associated steatohepatitis, ITPR3-mediated calcium release activates NLRP3-dependent macrophage pyroptosis, exacerbating disease 7. ITPR3 loss in SMARCA4/2-deficient cancers impairs chemotherapy-induced apoptosis by restricting calcium transfer to mitochondria 8.