Anionic phospholipids (PS)

Anionic phospholipids, primarily phosphatidylserine (PS), are essential membrane components typically restricted to the inner leaflet of the plasma membrane in healthy cells by ATP-dependent flippases (Birge et al., 2016). Under conditions of cellular stress, apoptosis, or oncogenic transformation, these lipids are translocated to the outer leaflet, where they become accessible to the extracellular environment (Thorpe, 2010). This externalization acts as a 'global' biomarker for the tumor microenvironment, appearing on both tumor cells and the associated vascular endothelium (Gerber et al., 2015). Exposed anionic phospholipids function as potent immunosuppressive signals, engaging inhibitory receptors on macrophages and dendritic cells to suppress anti-tumor immunity (Freitas et al., 2022). Therapeutic agents such as bavituximab target these exposed lipids to reverse immunosuppression and induce antibody-dependent cellular cytotoxicity (ADCC) against the tumor (Gerber et al., 2015). Additionally, many enveloped viruses exploit anionic phospholipid exposure to enter host cells through a process known as apoptotic mimicry (Amara & Mercer, 2015). Targeting this class of lipids provides a broad-spectrum strategy for treating various cancers and viral infections by exploiting a fundamental loss of membrane asymmetry.

Other names

Negatively charged phospholipidsPhosphatidylserinePhosphatidylinositolPhosphatidic acidPhosphatidylglycerolExposed anionic phospholipids

Drugs targeting anionic phospholipids primarily bind to phosphatidylserine (PS) that has flipped to the outer leaflet of the cell membrane. This binding, often mediated by cofactors like beta-2-glycoprotein I, triggers antibody-dependent cellular cytotoxicity (ADCC), reverses PS-induced immunosuppression by blocking inhibitory signaling to myeloid cells, and disrupts tumor vasculature (Thorpe, 2010; Birge et al., 2016).