Plasma membrane phospholipids of tumor cells

Plasma membrane phospholipids of tumor cells, particularly externalized phosphatidylserine (PS), represent a unique class of therapeutic targets characterized by the loss of membrane asymmetry in the tumor microenvironment. In healthy cells, PS is strictly maintained on the inner leaflet of the plasma membrane by ATP-dependent flippases; however, in response to stressors such as hypoxia, acidity, and oxidative stress, PS is externalized to the outer leaflet of both tumor cells and tumor-associated vascular endothelium (Thorpe, 2010). This externalized PS acts as a potent immunosuppressive 'immune checkpoint,' engaging receptors on immune cells to promote a 'do not eat' signal and polarize macrophages toward a pro-tumor M2 phenotype (Birge et al., 2016). Therapeutic strategies involve using monoclonal antibodies like bavituximab or lipid-binding complexes like SapC-DOPS to mask these phospholipids or trigger immune-mediated destruction of the tumor (He et al., 2009). By targeting the membrane itself rather than a specific protein, these therapies offer a broad-spectrum approach that may be less susceptible to the mutational escape mechanisms common in traditional targeted treatments. This target is currently being explored for its potential to enhance the efficacy of existing immunotherapies and chemotherapy regimens.

Other names

Tumor-associated phospholipidsExternalized phosphatidylserineAnionic phospholipidsTumor cell membrane lipids

Therapeutic agents target externalized anionic phospholipids, primarily phosphatidylserine (PS), which are normally sequestered in the inner leaflet of healthy cells but become exposed on the outer surface of tumor cells and tumor-associated vascular endothelium. Binding to these phospholipids can induce antibody-dependent cellular cytotoxicity (ADCC), disrupt tumor blood vessels, or block PS-mediated immunosuppressive signaling through TAM receptors (Tyro3, Axl, and MerTK), thereby re-polarizing the tumor microenvironment from an anti-inflammatory to a pro-inflammatory state (Birge et al., 2016; Thorpe, 2010).