Phosphatidylserine Externalization in Cancer: Biology, Immune Suppression, and Emerging Theragnostic Strategies.

Phosphatidylserine (PS) externalization is a conserved membrane stress signal that becomes chronically dysregulated in cancer cells and tumor-associated endothelium. In vivo, PS does not exist as a free lipid signal but is presented in specific membrane-associated forms, including apoptotic or stressed cell surfaces, PS-rich extracellular vesicles, and circulating lipid particles. Unlike apoptosis-associated transient PS exposure, malignant PS externalization arises from metabolic rewiring, oxidative stress, epigenetic silencing of flippases, and microenvironmental cues, creating an immunosuppressive interface across the tumor-host boundary. This review synthesizes mechanistic, immunological, and clinical evidence on PS biology, including its roles in tumor immune evasion, extracellular vesicle-mediated systemic suppression, and vascular remodeling. We further summarize the development and evaluation of PS-targeted therapeutic platforms-such as bavituximab, SapC-DOPS/BXQ-350, and PS-directed imaging agents-and highlight their translational potential in combination with radiotherapy, chemotherapy, and checkpoint inhibitors. Chronic PS externalization, as manifested through distinct cellular and vesicular carriers, represents a unifying biomarker of tumor stress, immune suppression, and therapeutic vulnerability, offering a next-generation axis for theragnostic cancer management.