PIK3IP1 is a transmembrane protein that functions as a negative regulator of the phosphatidylinositol 3-kinase (PI3K) pathway 1. It directly binds to the p110 catalytic subunit of PI3K to inhibit its activity 1. PIK3IP1 also inhibits T-cell receptor (TCR) signaling by mediating degradation of SLP76 through its extracellular oligomerization 2. In cancer biology, PIK3IP1 is frequently downregulated in tumors and acts as a tumor suppressor 1. Its reduced expression in mantle cell lymphoma and ovarian cancers correlates with disease progression 34. Restoring PIK3IP1 expression through EZH2 inhibition or LSD1 downregulation suppresses cancer cell proliferation and metastasis by blocking PI3K/Akt signaling 45. PIK3IP1 also serves as a critical immune checkpoint regulator. Deletion of Pik3ip1 enhances NK cell and T-cell antitumor immunity while reducing exhaustion markers 62. Conversely, high PIK3IP1 expression maintains immune cell quiescence and inhibits inflammatory responses, contributing to autoimmune disease severity 1. The aryl hydrocarbon receptor activates Pik3ip1 transcription in T cells to suppress PI3K/Akt/mTOR signaling and restrict effector T-cell activation in autoimmune hepatitis 7. PIK3IP1 expression is regulated by transcription factors, epigenetic modifiers, and microRNAs.