PI3Kγ (PIK3CG)

Class

Small molecule kinase inhibitor (immuno-oncology)

Pathway

PI3K/AKT/mTOR signaling; reprograms tumor-associated macrophages from an immunosuppressive M2 to pro-inflammatory M1 phenotype

PI3Kγ (encoded by PIK3CG) is one of four isoforms of phosphoinositide 3-kinase, a family of enzymes that convert membrane lipids into second messengers activating the AKT/mTOR signaling pathway, which governs cell survival, growth, and migration. Unlike the broadly expressed alpha and beta isoforms, PI3Kγ is enriched in immune cells, particularly myeloid cells such as macrophages and neutrophils, where it relays signals from G-protein-coupled receptors that control chemotaxis and activation state. In many solid tumors, macrophages that infiltrate the tumor microenvironment adopt an immunosuppressive, tissue-remodeling phenotype (often termed M2-like) that shields cancer cells from immune attack and supports invasion. Inhibiting PI3Kγ signaling in these cells can shift them toward a pro-inflammatory, tumoricidal phenotype (M1-like), potentially restoring immune surveillance and complementing therapies that reactivate T-cell function. Because this isoform's expression is largely restricted to hematopoietic cells rather than the epithelial and metabolic tissues where other PI3K isoforms dominate, targeting it selectively is intended to modulate tumor immunity without broadly disrupting insulin signaling or other physiological PI3K-dependent processes. This mechanism is being explored across cancers characterized by immunosuppressive myeloid infiltration and resistance to immune checkpoint blockade.