PIK3CD encodes the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), a lipid kinase that phosphorylates phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) 12. PIP3 recruits PH domain-containing proteins like AKT1 to the membrane, activating signaling cascades controlling cell growth, survival, proliferation, and migration. PIK3CD is essential for adaptive immunity: it mediates B-cell receptor signaling, proliferation, cytokine production, and antibody class switching 3; mediates T-cell receptor signaling, T-cell migration, and memory formation 4; and contributes to natural killer cell development and activation. Heterozygous gain-of-function PIK3CD mutations cause Activated PI3Kδ Syndrome (APDS1), a primary immunodeficiency characterized by recurrent respiratory infections, lymphoproliferation (70.4% of patients), hyper-IgM syndrome (48.1%), and autoimmunity 3. APDS patients show decreased B and CD4+ T cells and elevated malignancy risk (12.8%) 3. PIK3CD GOF mutations impair cytotoxic CD8+ T and NK cell differentiation, inducing premature exhaustion and reducing capacity to kill EBV-infected cells 5. Conversely, base-editing screens identified PIK3CD gain-of-function variants that enhance T-cell signaling and anti-tumor cytotoxicity in engineered T cells 67, suggesting therapeutic potential. The FDA-approved PI3Kδ inhibitor leniolisib rescues aberrant signaling in PIK3CD GOF T cells 7.