Tumor cell membrane phospholipids

Tumor cell membrane phospholipids, specifically anionic species like phosphatidylserine (PS), serve as distinct biomarkers and therapeutic targets due to the loss of membrane asymmetry in malignant cells (Birge et al., 2016, Nature Reviews Cancer). In healthy cells, PS is actively sequestered on the inner leaflet of the plasma membrane by flippase enzymes; however, the tumor microenvironment—characterized by hypoxia, acidity, and oxidative stress—inactivates these enzymes and triggers scramblases that expose PS on the cell surface (Thorpe, 2010, Vascular Health and Risk Management). This externalized PS acts as a global immunosuppressive signal, or immune checkpoint, by binding to receptors on myeloid cells and inhibiting the pro-inflammatory response (Gerber et al., 2018, Journal for ImmunoTherapy of Cancer). Therapeutic agents such as the monoclonal antibody bavituximab and the nanovesicle BXQ-350 are designed to bind these exposed phospholipids to either reverse immune evasion or directly induce tumor cell death (Bexion Pharmaceuticals, 2024; Oncologie, Inc., 2023). Because this phospholipid exposure is also prevalent on the tumor-associated vascular endothelium, these targets offer a dual mechanism for disrupting both the tumor cells and their blood supply. Consequently, targeting tumor cell membrane phospholipids represents a promising strategy for enhancing the efficacy of existing immunotherapies and overcoming resistance in the tumor microenvironment (Belzile et al., 2018, Frontiers in Immunology).

Other names

Tumor-associated phospholipidsExternalized phosphatidylserineAnionic phospholipids of the tumor membraneCancer cell surface lipids

Drugs targeting tumor cell membrane phospholipids primarily recognize externalized phosphatidylserine (PS) on the outer leaflet of the plasma membrane. This binding can block PS-mediated immunosuppressive signaling to macrophages and T-cells, induce antibody-dependent cellular cytotoxicity (ADCC), or facilitate the selective delivery of therapeutic agents to the tumor microenvironment (Birge et al., 2016; Thorpe, 2010).