Phosphatidylserine (PS)

Phosphatidylserine (PS) is an anionic phospholipid that is normally sequestered in the inner leaflet of the plasma membrane of healthy cells by the action of ATP-dependent flippases. Upon the induction of apoptosis or in response to cellular stress within the tumor microenvironment, PS is externalized to the outer leaflet by the activation of scramblases and the inactivation of flippases (Birge et al., 2016). Once exposed, PS acts as a critical 'eat-me' signal for phagocytic clearance and functions as a potent immunosuppressive molecule that inhibits the activation of dendritic cells and T-cells. In many cancers, the constitutive exposure of PS on tumor cells and the tumor vasculature creates an 'on-demand' immune checkpoint that protects the tumor from immune surveillance. Therapeutic agents like bavituximab are designed to bind to exposed PS, thereby blocking its immunosuppressive signaling and promoting a pro-inflammatory environment that enhances anti-tumor immunity. Beyond oncology, exposed PS is also utilized as a biomarker for imaging cell death and as a target for treating certain viral infections that utilize PS-mediated entry mechanisms, a process known as apoptotic mimicry (Belzile et al., 2010).

Other names

Ptd-L-SerPhosphatidyl-L-serineExposed phosphatidylserineExternalized phosphatidylserineAnnexin V-binding phospholipid

Drugs targeting exposed phosphatidylserine primarily act by blocking its interaction with inhibitory receptors (such as TIM and TAM receptors) on immune cells, thereby reversing PS-mediated immunosuppression and promoting a pro-inflammatory response. Some agents also utilize exposed PS as a specific docking site to deliver cytotoxic payloads or imaging labels directly to apoptotic or stressed cells, or to induce antibody-dependent cellular cytotoxicity (ADCC) against tumor-associated blood vessels.