Phosphatidylserine-rich membranes (PS)

Phosphatidylserine (PS) is an anionic phospholipid typically sequestered in the inner leaflet of the plasma membrane by ATP-dependent flippases in healthy cells (Birge et al., 2016). In response to apoptosis, cellular stress, or malignant transformation, PS is externalized to the outer leaflet, creating PS-rich membranes that act as a global immunosuppressive signal in the tumor microenvironment (Belzile et al., 2018). These membranes are found on the surface of tumor cells, tumor-associated vascular endothelial cells, and many enveloped viruses, where they engage inhibitory receptors on myeloid cells to prevent an immune response (Gerber et al., 2015). Therapeutic strategies targeting PS-rich membranes, such as the monoclonal antibody bavituximab or saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles, aim to reverse this immune evasion or directly induce tumor cell death (Davis et al., 2016). By masking PS or targeting it for immune destruction, these therapies can enhance the activity of other treatments, such as checkpoint inhibitors and chemotherapy, while potentially offering a broad-spectrum approach to treating viral infections (Pereira et al., 2016).

Other names

PhosphatidylserinePS-exposed membranesAnionic phospholipidsExternalized phosphatidylserine

Drugs targeting PS-rich membranes typically work by binding to externalized phosphatidylserine, either directly or via a cofactor like beta-2-glycoprotein I, to induce antibody-dependent cellular cytotoxicity (ADCC), promote the repolarization of tumor-associated macrophages from an M2 to an M1 phenotype, or facilitate the targeted delivery of cytotoxic payloads (Birge et al., 2016; Pereira et al., 2016).