Phosphoinositide 3-kinase catalytic subunit gamma (PI3Kγ) (PI3Kγ)

Phosphoinositide 3-kinase catalytic subunit gamma (PI3Kγ) is a Class IB PI3K enzyme primarily expressed in hematopoietic cells, including neutrophils, macrophages, and mast cells [1, 4]. Unlike Class IA PI3Ks that respond to receptor tyrosine kinases, PI3Kγ is uniquely activated by G protein-coupled receptors (GPCRs) via Gβγ subunits, playing a pivotal role in leukocyte chemotaxis and inflammatory signaling [1, 2]. In oncology, PI3Kγ is a key regulator of the tumor microenvironment, where it promotes the recruitment and immunosuppressive polarization of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages [2, 3]. Therapeutic inhibition of PI3Kγ aims to reprogram these myeloid cells from an immunosuppressive M2-like state to a pro-inflammatory M1-like state, thereby enhancing anti-tumor T-cell activity and potentially overcoming resistance to checkpoint inhibitors [3, 5]. Clinical development of PI3Kγ inhibitors, such as eganelisib and the dual δ/γ inhibitor duvelisib, targets both hematologic malignancies and solid tumors, as well as chronic inflammatory conditions [5].

Other names

PIK3CGp110γp120-PI3KPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoformClass IB PI3K

Inhibition of the p110γ catalytic subunit to block the conversion of PIP2 to PIP3, thereby inhibiting downstream AKT signaling and modulating immune cell recruitment and polarization.